LDLR genetic markers associated with age of onset of Alzheimer&#39;s Disease

ABSTRACT

Haplotypes in the LDLR gene associated: with age of onset of Alzheimer&#39;s Disease are disclosed. Compositions and methods for detecting and using these LDLR haplotypes in a variety of clinical applications are disclosed. Such applications include articles of manufacture comprising compounds effective in delaying the age of onset of AD in individuals at risk for developing AD and having one of these LDLR haplotypes, methods and kits for predicting the age of onset of AD in an individual at risk for developing AD based upon his/her haplotype profile, and methods for delaying the age of onset of AD in individuals at risk for developing AD based upon their haplotype profile.

This application claims priority to U.S. Provisional Application No.60/538,607, filed Jan. 22, 2004, which is incorporated by reference inits entirety.

FIELD OF THE INVENTION

This invention relates to the fields of genomics and pharmacogenomics.More specifically, this invention relates to variants of the geneencoding low-density lipoprotein receptor (LDLR) and their associationwith age of onset of Alzheimer's Disease.

BACKGROUND OF THE INVENTION

Alzheimer's Disease (hereinafter “AD”) is a fatal degenerative disorderof the central nervous system that is characterized by profound memoryimpairment, emotional disturbance, and in late stages, personalitychanges (Bartolucci et al., Proteins 42:182-191 (2001)). Scientistsgenerally distinguish between sporadic and familial AD. Sporadic AD, alate-onset form of the disease, is the most common form of AD, andgenerally only occurs in people who are at least 65. Familial AD, anearly-onset form of the disease, and accounting for only about 5% of allAD cases, generally affects people between the ages of 30 and 65. Theaverage worldwide risk of developing any type of AD is about 5% by age65, 10 to 15% by age 75, and 20 to 40% by age 85. While the cause ofsporadic AD is unknown, genetic factors are believed to be involved, asevidenced by an increased risk of AD in individuals who have a familyhistory of AD (Devi et al., Arch. Neurol. 57:28-29 (2000)) or who haveone or more of several specific polymorphisms that have been correlatedwith increased risk for AD. Known genetic polymorphisms that are riskfactors for developing AD include the apolipoprotein E (APOE) ε4 allele(U.S. Pat. No. 5,508,167); the α1-antichymotrypsin (ACT) A allele (U.S.Pat. No. 5,773,220), and the interleukin-1 (IL-1) A 2,2 and IL-1B 2,2genotypes (U.S. Pat. No. 6,225,069 B1).

Another recently recognized risk factor for developing AD is a diagnosisof mild or minimal cognitive impairment (MCI), which is a conditioncharacterized by subtle cognitive deficits not severe enough to beclassified as true dementia, but in many patients, and perhaps all,represents an early stage of AD (see, e.g., Chertkow, Curr. Opin.Neurol. 15:401-407 (2002); Morris et al., Arch. Neurol. 58:397-405(2001); Almkvist et al., J. Neural Transm. Suppl. 54:21-29 (1998)). Ithas been suggested that if drug therapy were started when symptoms ofreduced cognitive function first appear, even before a clinicaldiagnosis of AD, it is possible that progression to AD could be delayedor prevented (Morris et al., supra). Several multicenter trials ofvarious pharmacological agents are underway to test this hypothesis(Petersen et al., Neurology 56:1133-1142 (2001)).

A positive outcome of these trials may have a significant societalimpact. In 1998, the annual cost in the United States for the care ofpatients with AD was about $40,000 per patient and it is estimated thatthere will be 14 million AD patients in the United States by the year2050 (Petersen et al., supra). Thus, a pharmacological treatment thatdelays the progression of AD by as little as a year could result in hugecost savings and provide afflicted individuals with additional time toplan for their future while their decision-making capacity is onlyminimally affected.

This potential for pharmacological intervention to delay the onset orprogression of AD will place increasing pressure on health careprofessionals to diagnose whether an individual has MCI or early stageAD. However, there is controversy surrounding the characterization anddefinition of MCI, and early symptoms of AD are frequently mistakenlyattributed to the normal aging process (Morris et al., supra; Petersenet al., supra). Thus, a need exists for improved methods of diagnosingMCI and early stage AD.

A gene that may be involved in the age of onset of AD is the geneencoding low-density lipoprotein receptor (LDLR), a cell-surfacereceptor that plays an important role in regulating plasma cholesterol(Brown et al., Science 232:34-47 (1986). The gene consists of 18 exons,and has been mapped to chromosomal band 19 p 13.1-p 13.3 (Lindgren etal., Proc. Natl. Acad. Sci. USA 82:8657-8671 (1985)). It has beendemonstrated that serum cholesterol is elevated prior to the onset ofAD, and gradually decreases over the course of the disease (Burns etal., Neurochem. Res. 28:979-986 (2003); Jarvick et al., Neurology45:1092-1096 (1995)). The formation of properly functioning synapses byneurons requires the presence of astrocyte-derived cholesterol (Burns etal., supra). This cholesterol is transported to the neurons in thepresence of apolipoprotein E, a protein found mainly in astrocytes(Poierier et al., Mol. Brain Res. 11:97-106 (1991)). The gene encodingAPOE has three alleles, ε2, ε3, and ε4. In 1993, Corder et al.discovered that the APOE c4 allele is associated, in a dose-dependentmanner, with the age of onset of AD (Corder, E. H., et al., Science261:921-923 (1993)), a finding which has been confirmed by others (see,e.g., Murman et al., Dementia 7:251-255 (1996)).

Because of the possible involvement of LDLR in the cognitive deficitsobserved in MCI and early stages of AD, and the need for additional waysto identify people with these conditions, it would be useful to assessthe degree of variation in the LDLR gene in patients with AD and todetermine if any variants of this gene are associated with the age of ADonset.

SUMMARY OF THE INVENTION

Accordingly, the inventors herein have discovered a set of haplotypes inthe LDLR gene that are associated with the age of onset of AD. Theinventors have also discovered that the copy number of each of theseLDLR haplotypes affects the age of onset of AD. Testing for the presenceor absence, and copy number, of these haplotypes is useful forpredicting the age at which individuals who are at increased risk for ADare likely to develop AD and to help confirm a diagnosis of MCI or AD.Such knowledge will help individuals with MCI or AD, as well as theirphysicians and families, make therapy and lifestyle decisions. Inaddition, the correlation of certain LDLR haplotypes with age of ADonset indicates that variation in the LDLR gene should be considered inthe development and clinical trials of drugs for treating MCI, AD andother neurodegenerative disorders. This correlation also provides abasis for pursuing LDLR as a target for drugs designed to treatcognitive disorders such as MCI, AD and other neurological diseases orconditions. The LDLR haplotypes are shown in Table 1 below. TABLE 1 LDLRHaplotypes Having Association with Age of Onset of Alzheimer's DiseaseHap- lo- Polymorphic Site (PS)¹ type 1 2 3 4 5 6 7 8 9 10 11 12 13 14(1) T G G (2) T G T (3) T G C G (4) T G G T (5) T G G (6) T G G G (7) TG T T (8) T G G C (9) T G C G (10) T G G G (11) T G T G (12) T G T G(13) T G C G (14) T G C T (15) T G T (16) T G G T (17) T G G G (18) T GC G (19) T G C T (20) C T G G (21) T G T G (22) T G T C (23) T G C G(24) T G A G (25) T G G T (26) C T G T (27) C T G G (28) T G C (29) T GT C (30) T G G C (31) T G A G (32) T G T A (33) T G C C (34) C T G T(35) T G G G (36) C T G C (37) T G G G (38) T G T G (39) T G T A (40) TG C A (41) T G G T (42) T G G G (43) T G T G (44) T G G G (45) T G T G(46) C C C (47) C C G C (48) C C C A (49) T G G (50) T G G C (51) T G GA (52) T G G G (53) T G G G (54) C T G G (55) G T A G (56) G T A G (57)G T A (58) G T T A (59) G G T A (60) G T G A (61) G C T A (62) G G T A(63) G C T A (64) C G T A (65) G G T A (66) C G G A (67) G G A (68) G GC A (69) G G G A (70) G G G A (71) C C G C (72) C C C G (73) G T G (74)G T G G (75) G T T G (76) G G T G (77) G T G G (78) G C T G (79) G C T G(80) G G T G (81) G C T G (82) G T G G (83) G C T G (84) G G T G (85) GT G (86) G G T G (87) G T T G (88) G G T G (89) G G T G (90) G T (91) GG C T (92) G G T (93) G G T (94) G G C T (95) G C C T (96) G C T (97) GT T G (98) G G T G (99) G G T T (100) G T C T (101) G G T C (102) G G TG (103) G G T G (104) G C T G (105) G G G T (106) G G C T (107) G G C T(108) G T G (109) G C T (110) G G T T (111) G G G T (112) G T C T (113)G T T (114) G G T C (115) G G T (116) G C T G (117) G G A G (118) G G AG (119) G G C A (120) C G T G (121) C G T G (122) C C A (123) C C A C(124) C C G A (125) C C A A (126) C G T (127) C G G T (128) C G T G(129) C G C T (130) C G G T (131) C G G T (132) C G T T (133) C G C T(134) C C (135) C G C A (136) C C A (137) C G C (138) G G (139) G G G(140) G G G G (141) G G G (142) G G G C (143) G G C (144) G G C G (145)C A C G (146) C A C G (147) T G (148) T G G A (149) C T G G (150) T G G(151) T G C A (152) T G C (153) T G G A (154) T G G (155) C T G G (156)C T G C (157) T G C G (158) C T G A (159) C T G (160) T G A (161) T G GG (162) T G G C (163) C G C (164) C G C A (165) C G G C (166) C C (167)C C A (168) C G C (169) C G C A (170) C A (171) C A C A (172) C G A A(173) C G A C (174) C A A (175) C A C (176) C G A (177) C G G (178) C GG G (179) C G G G (180) C G G C (181) G G G (182) G G G (183) G G G G(184) G G C G (185) G G C G (186) G G G G (187) G G C G (188) G G C G(189) G G G G (190) G G G G (191) G G G G (192) C C G A (193) G G C(194) G G G C (195) G G C G (196) G G C C (197) C C C G (198) C C C G(199) C C A G (200) C G C (201) C G C A (202) C G G C (203) T A G (204)T A G (205) T T A G (206) G T A G (207) T G A G (208) G T A G (209) G TA G (210) C T A G (211) C T A G (212) C T A G (213) T T A G (214) G T AG (215) T G A G (216) T A G G (217) G T A G (218) G T A G (219) C T A G(220) C T A G (221) C T A G (222) C C G (223) C C G A (224) C G C G(225) T A (226) T T G A (227) C T A (228) C C T A (229) G T G A (230) GT C A (231) T C T A (232) G T G A (233) G T G A (234) C T G A (235) G CT A (236) C T T A (237) C G T A (238) G C T A (239) C T G A (240) C G TA (241) C C T A (242) C T A (243) G T T A (244) G T T A (245) T C T A(246) G G T A (247) G G T A (248) G C T A (249) T T A (250) G T C A(251) G T A (252) C T G A (253) T G A (254) G C T A (255) G T A (256) CG T A (257) G T A (258) C C T A (259) C T A (260) C G G G (261) C G G G(262) C G G C (263) C G C G (264) C G A (265) G A (266) C G G A (267) GG A (268) C G G A (269) G C A (270) C G C A (271) G C G A (272) G G G A(273) G G A (274) G G C A (275) C C G (276) C C G A (277) C G C G (278)C G A (279) C G A A (280) C G A C (281) C G G A (282) A C G (283) G A CG (284) A C C G (285) A C G G (286) G A C G (287) A C A G (288) A C G(289) A C C G (290) A C A G (291) C A C G (292) C A C G (293) A C G G(294) A C G G (295) C A G (296) C A G A (297) C A C G (298) C G A G(299) T G (300) T G (301) G T C G (302) G T G (303) G T C G (304) G T TG (305) G T G G (306) T T G G (307) G C T G (308) T G G G (309) G T G(310) C T G G (311) G G T G (312) G T G G (313) G T T G (314) G C T G(315) T G G (316) G T G G (317) G C T G (318) C T G G (319) G T G (320)T T G G (321) G G T G (322) G C T G (323) C T G G (324) T C T G (325) GG T G (326) T T G (327) T G G (328) G T G G (329) G T G G (330) G T T G(331) T T G G (332) C T G (333) C T G G (334) T C T G (335) G C T G(336) C C T G (337) C T G G (338) T C T G (339) G G T G (340) G T G(341) T T G (342) C T G (343) G C T G (344) T G G (345) G T G G (346) GT T G (347) C T G (348) C T G G (349) T C T G (350) G C T G (351) G T GG (352) C C T G (353) G T C G (354) G T G (355) C T G (356) G C T G(357) G T G (358) G T C G (359) G T G G (360) G T G G (361) T (362) T CT G (363) G C T G (364) G T C T (365) T T (366) C C T G (367) T C C T(368) G G T C (369) T G (370) G T T (371) G T G (372) C T (373) T C T(374) C T G (375) G C T (376) G C T G (377) G T C T (378) C C T (379) GT (380) G C C T (381) C T (382) G C T (383) G T C G (384) G T G (385) GT C (386) G T C G (387) G T (388) G T C C (389) G T C (390) G T T G(391) G T C T (392) G C T G (393) G T T (394) G T G (395) G G T T (396)G G T G (397) G T C T (398) G C T (399) G C T G (400) G G C T (401) G T(402) G C C T (403) G G T (404) G C T (405) G G C T (406) T C T G (407)G G T G (408) T T G (409) G G T C (410) G T T G (411) G G T (412) T C T(413) C T G (414) C (415) G C A (416) C A (417) G C (418) G C A G (419)G A G (420) G C A G (421) G A G G (422) G C A G (423) G G A G (424) G AG (425) C G A G (426) G G A G (427) C G A G (428) G G A G (429) G C A G(430) G G A G (431) C G C G (432) C C G (433) C C G G (434) G C C G(435) C C G G (436) G C C G (437) C C G G (438) C C C G (439) C C A G(440) C C G (441) C C C G (442) C C A G (443) G C (444) G G C A (445) GC A (446) G G C (447) C G C A (448) G C A (449) G G C A (450) G C G A(451) G C C A (452) C A (453) C G A C (454) C A A (455) C A C (456) C GA (457) C A C A (458) C G A A (459) C G A (460) C G A A (461) C G A C(462) C G G A (463) C G G (464) C G G (465) G C G G (466) C G G G (467)G C G G (468) C G A G (469) C C G G (470) C G A G (471) C C G G (472) CT G (473) C T G (474) C C T G (475) C G T G (476) C G T G (477) C T G G(478) C G T G (479) C T T G (480) C G T G (481) C G T G (482) C T T G(483) C G T G (484) C T G G (485) C C T G (486) C C T G (487) C T G G(488) C C T G (489) C T (490) C T C T (491) C G T G (492) C C T G (493)C G C T (494) C G C T (495) C G T (496) C C T (497) C G T T (498) C G TT (499) C T C T (500) C G G T (501) C G T C (502) C G T G (503) C G G T(504) C G C T (505) C T T (506) C G T (507) C G T C (508) C C T G (509)C T G (510) C G C T (511) C G T (512) C C C T (513) C C T (514) C T T G(515) C G T G (516) T G (517) T G T (518) T G T C (519) T G C G (520) CT G (521) C T C C (522) T C C T (523) T T G (524) T G G G (525) T G A G(526) C T T G (527) C T G G (528) T T G G (529) T T T G (530) C T T A(531) C T A G (532) T T A G (533) T T T A (534) T G C T (535) T C G(536) T G G (537) T C A (538) T G G G (539) T G A G (540) T T C G (541)T T (542) T G T G (543) C T C G (544) C T G C (545) T G C T (546) C T TG (547) C T T A (548) T G C C (549) T G T G (550) T C C G (551) T G T A(552) T T C G (553) T G G C (554) T G G G (555) T T G G (556) T A G G(557) T T A G (558) C T C G (559) T G C G (560) C T T C (561) T C T G(562) T T C T (563) C T G T (564) C T G G (565) T G T G (566) T C C(567) T T G (568) T G G (569) T G T C (570) T G C G (571) T A G (572) TT A (573) T C G G (574) T G C G (575) C T T C (576) T G T G (577) T C TG (578) T G T A (579) T T C T (580) C T G G (581) T T G G (582) C T A G(583) T T A G (584) T G T T (585) C T C T (586) T G T C (587) T G C G(588) C T G T (589) T G G G (590) T C G (591) T C G A (592) T G C (593)T C G G (594) T G A G (595) T T C G (596) T G G G (597) T G G T (598) TT G (599) T G C T (600) T T A (601) T G T G (602) T G G G (603) C T C G(604) C T T G (605) T T T G (606) C T C T (607) T C G (608) T T C (609)T T C G (610) C T G C (611) T G C T (612) T G T (613) T G G (614) C T CG (615) T C T G (616) T G G T (617) C T G G (618) T G T G (619) C T T G(620) C T T T (621) T T C (622) T C C G (623) T G G (624) T G C G (625)T C C A (626) T G T G (627) T A G (628) C T C (629) T G A G (630) T T GA (631) T T G G (632) T C T (633) T C T G (634) C T G G (635) T G T(636) T G C G (637) T C G (638) T T G (639) T C G G (640) T C T (641) TG C G (642) T C A G (643) T G G G (644) T G C A (645) C T G T (646) T GT T (647) T G T G (648) C T T G (649) C T G G (650) T T G A (651) T T GG (652) T T T G (653) T G C (654) T C G (655) T C G G (656) T G G G(657) T C A G (658) T T C G (659) T T C A (660) T G C C (661) T G G(662) C T T (663) C T G (664) T T T (665) T T G (666) T G T G (667) T GG G (668) T G A G (669) T G T A (670) C T G T (671) T C (672) C T T G(673) T G G (674) T T C G (675) T G T G (676) T T C A (677) T G A G(678) C T C G (679) C T G G (680) C T C A (681) T C T G (682) T C T A(683) C T T (684) T G T G (685) T G T A (686) T G T (687) T C C G (688)T T G (689) T G G (690) T T C C (691) T C G G (692) T T G G (693) T C AG (694) T T A G (695) T C T G (696) T G T G (697) T C T A (698) T G T C(699) T G C G (700) T G (701) T G C G (702) T G C A (703) T C G G (704)T C A G (705) G (706) G C G (707) G G (708) G G G (709) G G (710) G G C(711) G G C G (712) G C (713) A (714) G A C A (715) A C A (716) G A A(717) G A C (718) A A (719) A C (720) G A (721) C G (722) C C G (723) GC A G (724) C A G G (725) C C A G (726) G C G G (727) C A G (728) C G CG (729) C C G G (730) G C G (731) C G G (732) C C G (733) C G (734) G CA G (735) C C A G (736) C A G (737) C G C G (738) G C G (739) C G A G(740) G C C G (741) G C C G (742) T G (743) T G C G (744) T G G G (745)C T G A (746) T G A (747) C T G (748) T G G C (749) T G G A (750) C T GG (751) T G G (752) T G C A (753) T G G A (754) T G G (755) T G C (756)C T G C (757) C T G G (758) G A (759) G A C A (760) G G A A (761) G G AC (762) G A A (763) G A C (764) G G A¹The absence of a PS entry for a haplotype indicates that the PS is notpart of the marker.

If an individual has (a) one copy or two copies of any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) zero copies or one copy of any of haplotypes (46)-(48),(71), (72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, that individual isdefined as having an “age of onset marker I” and is more likely to havea later age of onset of AD than an individual having (a) zero copies ofany of haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133),(138)-(144), (147)-(162), (177)-(191), (193)-(195), (203)-221),(225)-(262), (264)-(274), (299)-(413), (418)-(430), (447)-(451),(472)-(712), and (742)-(757) in Table 1, or (b) two copies of any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, such individual being defined as having an “age of onset markerII.” Information about the composition of each of haplotypes (1)-(764)in Table 1, namely the location in the LDLR gene of each of thepolymorphic sites (PSs), and the identity of the reference and variantallele at each PS, can be found in Table 2, shown below. TABLE 2Polymorphic Sites Identified in the LDLR Gene of Caucasian Individualswith Alzheimer's Disease Position PS in FIG. 1/ Reference Variant NumberPoly ID¹ Location SEQ ID NO: 1 Allele Allele 1 8979110 intron 1 1703 C T2 8979118 exon 2 12203 T C 3 8979150 intron 5 18873 G C 4 8979160 exon 823591 G A 5 8979200 intron 10 25782 A G 6 8979220 intron 11 28361 C T 78979230 intron 11 28771 A C 8 8979232 exon 12 28845 C T 9 8979234 exon12 28893 T C 10 8979246 exon 14 32455 G A 11 8979248 intron 14 32494 G A12 8979252 intron 14 32626 A G 13 31334142 intron 17 43101 G A 1431334144 intron 17 43168 G A¹The Poly ID is a unique identifier assigned to the indicated PS byGenaissance Pharmaceuticals, Inc., New Haven, CT.

addition, as described in more detail below, the inventors believe thatadditional haplotypes may readily be identified based on linkagedisequilibrium between any of the above LDLR haplotypes and anotherhaplotype located in the LDLR gene or another gene, or between an alleleat one or more of the PSs in the above haplotypes and an allele atanother PS located in the LDLR gene or another gene. In particular, suchhaplotypes include haplotypes that are in linkage disequilibrium withany of haplotypes (1)-(764) in Table 1, hereinafter referred to as“linked haplotypes,” as well as “substitute haplotypes” for any ofhaplotypes (1)-(764) in which one or more of the polymorphic sites (PSs)in the original haplotype is substituted with another PS, wherein theallele at the substituted PS is in linkage disequilibrium with theallele at the substituting PS.

In one aspect, the invention provides methods and kits for determiningwhether an individual has an age of onset marker I or an age of onsetmarker II. In one embodiment, a method is provided for determiningwhether an individual has an age of onset marker I or an age of onsetmarker II comprising determining whether the individual has (a) one copyor two copies, or zero copies of any of (i) haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) zero copies or one copy, or two copies of any of (i)haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, (ii) a linked haplotype for any of haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1.

In another embodiment of the invention, a method is provided forassigning an individual to a first or second age of onset marker groupcomprising determining whether the individual has (a) one copy or twocopies, or zero copies of any of (i) haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii)a linked haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, and(iii) a substitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy, or two copies of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1; and assigning the individual to an age ofonset marker group based on the copy number of that haplotype. Theindividual is assigned to the first age of onset marker group if theindividual has (a) one copy or two copies of any of (i) haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) zero copies or one copy of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and is assigned to the second age of onsetmarker group if the individual has (a) zero copies of any of (i)haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144),(147)-(162), (177)-(191), (193)-(195), (203)-221), (225)-(262),(264)-(274), (299)-(413), (418)-(430), (447)-(451), (472)-(712), and(742)-(757) in Table 1, (ii) a linked haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) two copies of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764), (ii) a linked haplotype forany of haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137),(145), (146), (163)-(176), (192), (196)-(202), (222)-(224), (263),(275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741), and(758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1.

One embodiment of a kit for determining whether an individual has an ageof onset marker I or an age of onset marker II comprises a set ofoligonucleotides designed for identifying at least one of the allelespresent at each PS in a set of one or more PSs. The set of one or morePSs comprises the set of one or more PSs for any of the haplotypes inTable 1, the set of one or more PSs for a linked haplotype for any ofthe haplotypes in Table 1, or the set of one or more PSs for asubstitute haplotype for any of the haplotypes in Table 1. In a furtherembodiment, the kit comprises a manual with instructions for performingone or more reactions on a human nucleic acid sample to identify theallele(s) present in the individual at each PS in the set anddetermining if the individual has an age of onset marker I or an age ofonset marker II based on the identified allele(s).

The invention further provides a method for delaying the onset of AD inan individual at risk for developing AD. The method comprisesdetermining whether the individual has an age of onset marker I or anage of onset marker II and making a treatment decision for theindividual based on the results of the determining step. If theindividual is determined to have an age of onset marker I, then thetreatment decision is to prescribe to the individual a compoundeffective in delaying the onset of AD, wherein the compound isprescribed to the individual at an age that is below that of the lowerconfidence interval of the least square mean of age of onset for the ageof onset marker I. If the individual is determined to have an age ofonset marker II, then the treatment decision is to prescribe to theindividual a compound effective in delaying the onset of AD, wherein thecompound is prescribed to the individual at an age that is below that ofthe lower confidence interval of the least square mean of age of onsetfor the age of onset marker II. According to Table 8 below, the lowerconfidence interval of the least square mean of age of onset for an ageof onset marker I ranges from 72.4 to 75.3, and the lower confidenceinterval of the least square mean of age of onset for an age of onsetmarker II ranges from 64.1 to 71.3.

In yet another embodiment, the invention provides a method forpredicting an individual's age of onset of AD. The method comprisesdetermining whether the individual has an age of onset marker I or anage of onset marker II and making an prediction based on the results ofthe determining step. According to Table 8 below, if the individual isdetermined to have an age of onset marker I, then the prediction is thatthe individual's age of onset of AD will be between 71.9 and 81, and ifthe individual is determined to have an age of onset marker II, then theprediction is that the individual's age of onset of AD will be between59.4 and 72.9.

In other aspects, the invention provides (i) a method for seekingregulatory approval for marketing a pharmaceutical formulationcomprising, as at least one active ingredient, a compound effective indelaying the onset of AD, to a population at risk for developing AD,wherein the population is partially or wholly defined by having an ageof onset marker I or an age of onset marker II, (ii) an article ofmanufacture comprising the pharmaceutical formulation, (iii) a methodfor manufacturing a drug product comprising the pharmaceuticalformulation, and (iv) a method for marketing the drug product.

The method for seeking regulatory approval comprises conducting at leastone clinical trial which comprises administering the pharmaceuticalformulation to first and second groups of individuals at risk fordeveloping AD, and administering a placebo to third and fourth groups ofindividuals at risk for developing AD, wherein each individual in thefirst and third groups has an age of onset marker I, and each individualin the second and fourth groups has an age of onset marker II,demonstrating that the first group exhibits a later onset of AD than thethird group, and demonstrating that the second group exhibits a lateronset of AD than the fourth group, and filing with a regulatory agencyan application for marketing approval of the pharmaceutical formulationwith a label stating that the pharmaceutical formulation is indicatedfor delaying the onset of AD in a population at risk for developing AD.In preferred embodiments, the regulatory agency is the United StatesFood and Drug Administration (FDA) or the European Agency for theEvaluation of Medicinal Products (EMEA), or a future equivalent of theseagencies.

In one embodiment, the article of manufacture comprises thepharmaceutical formulation and at least one indicium identifying apopulation for whom the pharmaceutical formulation is indicated, whereinthe identified population is at risk for developing AD and is partiallyor wholly defined by having an age of onset marker I or an age of onsetmarker II, wherein a trial population of individuals having an age ofonset marker I exhibit a later age of onset of AD than a trialpopulation having an age of onset marker II. Another embodiment of thearticle of manufacture comprises packaging material and thepharmaceutical formulation contained within the packaging material,wherein the packaging material comprises a label approved by aregulatory agency for the pharmaceutical formulation, wherein the labelstates that the pharmaceutical formulation is indicated for a populationat risk for developing AD that is partially or wholly defined by havingan age of onset marker I or an age of onset marker II, and preferablyfurther stating that a trial population of individuals having an age ofonset marker I exhibit a later age of onset of AD than a trialpopulation of individuals having an age of onset marker II. Preferably,the pharmaceutical formulation comprises, as at least one activeingredient, a compound effective in delaying the onset of AD.

The method for manufacturing the drug product comprises combining in apackage a pharmaceutical formulation comprising, as at least one activeingredient, a compound effective in delaying the onset of AD, and alabel which states that the drug product is indicated for a populationat risk for developing AD, wherein the population is partially or whollydefined by having an age of onset marker I or an age of onset marker II,wherein those members of the population having an age of onset marker Iexhibit a later age of onset of AD than those members of the populationhaving an age of onset marker II.

The method for marketing the drug product comprises promoting to atarget audience the use of the drug product for treating individuals whobelong to the defined population.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1A-1R illustrates a reference sequence for the LDLR gene(contiguous lines; SEQ ID NO:1), with the start and stop positions ofeach region of coding sequence indicated with a bracket ([ or ]) and thenumerical position below the sequence and the polymorphic site(s) andpolymorphism(s) identified in the patient cohort indicated by thevariant nucleotide positioned below the polymorphic site in thesequence.

Definitions

In the context of this disclosure, the terms below shall be defined asfollows unless otherwise indicated:

Allele—A particular form of a genetic locus, distinguished from otherforms by its particular nucleotide sequence, or one of the alternativepolymorphisms found at a polymorphic site.

Gene—A segment of DNA that contains the coding sequence for a protein,wherein the segment may include promoters, exons, introns, and otheruntranslated regions that control expression.

Genotype—An unphased 5′ to 3′ sequence of nucleotide pair(s) found at aset of one or more polymorphic sites in a locus on a pair of homologouschromosomes in an individual. As used herein, genotype includes afull-genotype and/or a sub-genotype as described below.

Genotyping—A process for determining a genotype of an individual.

Haplotype—A 5′ to 3′ sequence of nucleotides found at a set of one ormore polymorphic sites in a locus on a single chromosome from a singleindividual.

Haplotype pair—The two haplotypes found for a locus in a singleindividual.

Haplotyping—A process for determining one or more haplotypes in anindividual and includes use of family pedigrees, molecular techniquesand/or statistical inference.

Haplotype data—Information concerning one or more of the following for aspecific gene: a listing of the haplotype pairs in an individual or ineach individual in a population; a listing of the different haplotypesin a population; frequency of each haplotype in that or otherpopulations, and any known associations between one or more haplotypesand a trait.

Isolated—As applied to a biological molecule such as RNA, DNA,oligonucleotide, or protein, isolated means the molecule issubstantially free of other biological molecules such as nucleic acids,proteins, lipids, carbohydrates, or other material such as cellulardebris and growth media. Generally, the term “isolated” is not intendedto refer to a complete absence of such material or to absence of water,buffers, or salts, unless they are present in amounts that substantiallyinterfere with the methods of the present invention.

Locus—A location on a chromosome or DNA molecule corresponding to a geneor a physical or phenotypic feature, where physical features includepolymorphic sites.

Nucleotide pair—The nucleotides found at a polymorphic site on the twocopies of a chromosome from an individual.

Phased—As applied to a sequence of nucleotide pairs for two or morepolymorphic sites in a locus, phased means the combination ofnucleotides present at those polymorphic sites on a single copy of thelocus is known.

Polymorphic site (PS)—A position on a chromosome or DNA molecule atwhich at least two alternative sequences are found in a population.

Polymorphism—The sequence variation observed in an individual at apolymorphic site. Polymorphisms include nucleotide substitutions,insertions, deletions and microsatellites and may, but need not, resultin detectable differences in gene expression or protein function.

Polynucleotide—A nucleic acid molecule comprised of single-stranded RNAor DNA or comprised of complementary, double-stranded DNA.

Population Group—A group of individuals sharing a common ethnogeographicorigin.

Reference Population—A group of subjects or individuals who arepredicted to be representative of the genetic variation found in thegeneral population. Typically, the reference population represents thegenetic variation in the population at a certainty level of at least85%, preferably at least 90%, more preferably at least 95% and even morepreferably at least 99%.

Single Nucleotide Polymorphism (SNP)—Typically, the specific pair ofnucleotides observed at a single polymorphic site. In rare cases, threeor four nucleotides may be found.

Subject—A human individual whose genotypes or haplotypes or age of onsetto treatment or disease state are to be determined.

Treatment—A stimulus administered internally or externally to a subject.

Unphased—As applied to a sequence of nucleotide pairs for two or morepolymorphic sites in a locus, unphased means the combination ofnucleotides present at those polymorphic sites on a single copy of thelocus is not known.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Each age of onset marker of the invention is a combination of aparticular haplotype and the copy number for that haplotype. Preferably,the haplotype is one of the haplotypes shown in Table 1. The PS or PSsin these haplotypes are referred to herein as PS1, PS2, PS3, PS4, PS5,PS6, PS7, PS8, PS9, PS10, PS11, PS12, PS13, and PS14, and are located inthe LDLR gene at positions corresponding to those identified in FIG.1/SEQ ID NO:1 (see Table 2 for summary of PS1, PS2, PS3, PS4, PS5, PS6,PS7, PS8, PS9, PS10, PS11, PS12, PS13, and PS14 and locations). Indescribing the PSs in the age of onset markers of the invention,reference is made to the sense strand of a gene for convenience.However, as recognized by the skilled artisan, nucleic acid moleculescontaining a particular gene may be complementary double strandedmolecules and thus reference to a particular site or haplotype on thesense strand refers as well to the corresponding site or haplotype onthe complementary antisense strand. Further, reference may be made todetecting a genetic marker or haplotype for one strand and it will beunderstood by the skilled artisan that this includes detection of thecomplementary haplotype on the other strand.

As described in more detail in the examples below, the age of onsetmarkers of the invention are based on the discovery by the inventors ofassociations between certain haplotypes in the LDLR gene and the age ofonset of AD in a cohort of individuals diagnosed with AD.

In particular, the inventors herein discovered that a haplotypecomprising a thymine at PS2 and a guanine at PS4 (haplotype (147) inTable 1) affected the age of onset of AD of the patients participatingin the study. The group of patients having one copy or two copies ofthis haplotype experienced a later age of onset of AD than the patientgroup having zero copies of the haplotype.

In addition, the skilled artisan would expect that there might beadditional PSs in the LDLR gene or elsewhere on chromosome 19, whereinan allele at that PS is in high linkage disequilibrium (LD) with anallele at one or more of the PSs in the haplotypes comprising an age ofonset marker I or an age of onset marker II. Two particular alleles atdifferent PSs are said to be in LD if the presence of the allele at oneof the sites tends to predict the presence of the allele at the othersite on the same chromosome (Stevens, Mol. Diag. 4:309-17 (1999)). Oneof the most frequently used measures of linkage disequilibrium is Δ²,which is calculated using the formula described by Devlin et al.,Genomics 29:3112-22 (1995). Δ² is the measure of how well an allele X ata first PS predicts the occurrence of an allele Y at a second PS on thesame chromosome. The measure only reaches 1.0 when the prediction isperfect (e.g., X if and only if Y).

Thus, the skilled artisan would expect that all of the embodiments ofthe invention described herein may frequently be practiced bysubstituting any (or all) of the specifically identified LDLR PSs in anage of onset marker with another PS, wherein an allele at thesubstituted PS is in LD with an allele at the “substituting” PS. This“substituting” PS may be one that is currently known or subsequentlydiscovered and may be present in the LDLR gene, in a genomic region ofabout 100 kilobases spanning the LDLR gene, or elsewhere on chromosome19.

Further, the inventors contemplate that there will be other haplotypesin the LDLR gene or elsewhere on chromosome 19 that are in LD with oneor more of the haplotypes in Table 1 that would therefore also bepredictive of age of onset of AD. Preferably, the linked haplotype ispresent in the LDLR gene or in a genomic region of about 100 kilobasesspanning the LDLR gene. The linkage disequilibrium between thehaplotypes in Table 1 and such linked haplotypes can also be measuredusing Δ².

In preferred embodiments, the linkage disequilibrium between an alleleat a polymorphic site in any of the haplotypes in Table 1 and an alleleat a “substituting” polymorphic site, or between any of the haplotypesin Table 1 and a linked haplotype, has a Δ² value, as measured in asuitable reference population, of at least 0.75, more preferably atleast 0.80, even more preferably at least 0.85 or at least 0.90, yetmore preferably at least 0.95, and most preferably 1.0. A suitablereference population for this Δ² measurement is selected from apopulation with the distribution of its members reflecting the generalpopulation, a population with AD or AD risk factors, and the like.

LD patterns in genomic regions are readily determined empirically inappropriately chosen samples using various techniques known in the artfor determining whether any two alleles (either those occurring at twodifferent PSs or two haplotypes for two different multi-site loci) arein linkage disequilibrium (GENETIC DATA ANALYSIS II, Weir, SinauerAssociates, Inc. Publishers, Sunderland, Mass., 1996). The skilledartisan may readily select which method of determining LD will be bestsuited for a particular sample size and genomic region.

As described above and in the examples below, the age of onset markersof the invention are associated with differences in the age of onset ofAD. Thus, the invention provides a method and kit for determiningwhether an individual has an age of onset marker I or an age of onsetmarker II. An age of onset marker I is (a) one copy or two copies of anyof (i) haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133),(138)-(144), (147)-(162), (177)-(191), (193)-(195), (203)-221),(225)-(262), (264)-(274), (299)-(413), (418)-(430), (447)-(451),(472)-(712), and (742)-(757) in Table 1, (ii) a linked haplotype for anyof haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144),(147)-(162), (177)-(191), (193)-(195), (203)-221), (225)-(262),(264)-(274), (299)-(413), (418)-(430), (447)-(451), (472)-(712), and(742)-(757) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144),(147)-(162), (177)-(191), (193)-(195), (203)-221), (225)-(262),(264)-(274), (299)-(413), (418)-(430), (447)-(451), (472)-(712), and(742)-(757) in Table 1, or (b) zero copies or one copy of any of (i)haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1. An age of onset marker II is (a) zero copiesof any of (i) haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133),(138)-(144), (147)-(162), (177)-(191), (193)-(195), (203)-221),(225)-(262), (264)-(274), (299)-(413), (418)-(430), (447)-(451),(472)-(712), and (742)-(757) in Table 1, (ii) a linked haplotype for anyof haplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144),(147)-(162), (177)-(191), (193)-(195), (203)-221), (225)-(262),(264)-(274), (299)-(413), (418)-(430), (447)-(451), (472)-(712), and(742)-(757) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144),(147)-(162), (177)-(191), (193)-(195), (203)-221), (225)-(262),(264)-(274), (299)-(413), (418)-(430), (447)-(451), (472)-(712), and(742)-(757) in Table 1, or (b) two copies of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1.

In one embodiment, the invention provides a method for determiningwhether an individual has an age of onset marker I or an age of onsetmarker II. The method comprises determining whether the individual has(a) one copy or two copies, or zero copies of any of (i) haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) zero copies or one copy, or two copies of any of (i)haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1. Preferably, the method comprises determiningwhether the individual has one copy or two copies, or zero copies of anyof (a) haplotype (147) in Table 1, (b) a linked haplotype for haplotype(147) in Table 1, and (c) a substitute haplotype for haplotype (147) inTable 1.

In some embodiments, the individual is Caucasian and is at risk fordeveloping a cognitive disorder, such as mild to moderate dementia ofthe Alzheimer's type, dementia associated with Parkinson's Disease, MCI,a vascular dementia, and Lewy body dementia.

In another embodiment, the invention provides a method for assigning anindividual to a first or second age of onset marker group. The methodcomprises determining whether the individual has (a) one copy or twocopies, or zero copies of any of (i) haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii)a linked haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, and(iii) a substitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy, or two copies of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764),(ii) a linked haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, and (iii) a substitutehaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and assigning the individual to the firstage of onset marker group if the individual has (a) one copy or twocopies of any of (i) haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii) a linkedhaplotype for any of haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764), (ii) a linked haplotype forany of haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137),(145), (146), (163)-(176), (192), (196)-(202), (222)-(224), (263),(275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741), and(758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, and assigning the individual to the second age of onset markergroup if the individual has (a) zero copies of any of (i) haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) two copies of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764), (ii) a linked haplotype forany of haplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137),(145), (146), (163)-(176), (192), (196)-(202), (222)-(224), (263),(275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741), and(758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1.

In some embodiments, the individual is Caucasian and is at risk fordeveloping a cognitive disorder, such as mild to moderate dementia ofthe Alzheimer's type, dementia associated with Parkinson's Disease, MCI,a vascular dementia, and Lewy body dementia.

The presence in an individual of an age of onset marker I or an age ofonset marker II may be determined by a variety of indirect or directmethods well known in the art for determining haplotypes or haplotypepairs for a set of one or more PSs in one or both copies of theindividual's genome, including those discussed below. The genotype for aPS in an individual may be determined by methods known in the art or asdescribed below.

One indirect method for determining whether zero copies, one copy, ortwo copies of a haplotype is present in an individual is by predictionbased on the individual's genotype determined at one or more of the PSscomprising the haplotype and using the determined genotype at each siteto determine the haplotypes present in the individual. The presence ofzero copies, one copy, or two copies of a haplotype of interest can bedetermined by visual inspection of the alleles at the PS that comprisethe haplotype. The haplotype pair is assigned by comparing theindividual's genotype with the genotypes at the same set of PScorresponding to the haplotype pairs known to exist in the generalpopulation or in a specific population group or to the haplotype pairsthat are theoretically possible based on the alternative allelespossible at each PS, and determining which haplotype pair is most likelyto exist in the individual.

In a related indirect haplotyping method, the presence in an individualof zero copies, one copy, or two copies of a haplotype is predicted fromthe individual's genotype for a set of PSs comprising the selectedhaplotype using information on haplotype pairs known to exist in areference population. In one embodiment, this haplotype pair predictionmethod comprises identifying a genotype for the individual at the set ofPSs comprising the selected haplotype, accessing data containinghaplotype pairs identified in a reference population for a set of PSscomprising the PSs of the selected haplotype, and assigning to theindividual a haplotype pair that is consistent with the individual'sgenotype. Whether the individual has an age of onset marker I or an ageof onset marker II can be subsequently determined based on the assignedhaplotype pair. The haplotype pair can be assigned by comparing theindividual's genotype with the genotypes corresponding to the haplotypepairs known to exist in the general population or in a specificpopulation group, and determining which haplotype pair is consistentwith the genotype of the individual. In some embodiments, the comparingstep may be performed by visual inspection. When the genotype of theindividual is consistent with more than one haplotype pair, frequencydata may be used to determine which of these haplotype pairs is mostlikely to be present in the individual. If a particular haplotype pairconsistent with the genotype of the individual is more frequent in thereference population than other pairs consistent with the genotype, thenthat haplotype pair with the highest frequency is the most likely to bepresent in the individual. The haplotype pair frequency data used inthis determination is preferably for a reference population comprisingthe same ethnogeographic group as the individual. This determination mayalso be performed in some embodiments by visual inspection. In otherembodiments, the comparison may be made by a computer-implementedalgorithm with the genotype of the individual and the referencehaplotype data stored in computer-readable formats. For example, asdescribed in WO 01/80156, one computer-implemented algorithm to performthis comparison entails enumerating all possible haplotype pairs whichare consistent with the genotype, accessing data containing haplotypepairs frequency data determined in a reference population to determine aprobability that the individual has a possible haplotype pair, andanalyzing the determined probabilities to assign a haplotype pair to theindividual.

Typically, the reference population is composed of randomly selectedindividuals representing the major ethnogeographic groups of the world.A preferred reference population for use in the methods of the presentinvention consists of Caucasian individuals, the number of which ischosen based on how rare a haplotype is that one wants to be guaranteedto see. For example, if one wants to have a q % chance of not missing ahaplotype that exists in the population at a p % frequency of occurringin the reference population, the number of individuals (n) who must besampled is given by 2n=log(1-q)/log(1-p) where p and q are expressed asfractions. A preferred reference population allows the detection of anyhaplotype whose frequency is at least 10% with about 99% certainty. Aparticularly preferred reference population includes a 3-generationCaucasian family to serve as a control for checking quality ofhaplotyping procedures.

If the reference population comprises more than one ethnogeographicgroup, the frequency data for each group is examined to determinewhether it is consistent with Hardy-Weinberg equilibrium. Hardy-Weinbergequilibrium (Principles of Population Genomics, 3rd ed., Hartl, SinauerAssociates, Sunderland, Mass. (1997)) postulates that the frequency offinding the haplotype pair H₁/H₂ is equal to P_(H−W)(H₁/H₂)=2p(H₁)p(H₂)if H₁≠H₂ and P_(H−W)(H₁/H₂)=p(H₁)p(H₂) if H₁=H₂. A statisticallysignificant difference between the observed and expected haplotypefrequencies could be due to one or more factors including significantinbreeding in the population group, strong selective pressure on thegene, sampling bias, and/or errors in the genotyping process. If largedeviations from Hardy-Weinberg equilibrium are observed in anethnogeographic group, the number of individuals in that group can beincreased to see if the deviation is due to a sampling bias. If a largersample size does not reduce the difference between observed and expectedhaplotype pair frequencies, then one may wish to consider haplotypingthe individual using a direct haplotyping method such as, for example,CLASPER System™ technology ((U.S. Pat. No. 5,866,404), single moleculedilution, or allele-specific long-range PCR (Michalotos-Beloin et al.,Nucleic Acids Res. 24:4841-4843 (1996)).

In one embodiment of this method for predicting a haplotype pair for anindividual, the assigning step involves performing the followinganalysis. First, each of the possible haplotype pairs is compared to thehaplotype pairs in the reference population. Generally, only one of thehaplotype pairs in the reference population matches a possible haplotypepair and that pair is assigned to the individual. Occasionally, only onehaplotype represented in the reference haplotype pairs is consistentwith a possible haplotype pair for an individual, and in such cases theindividual is assigned a haplotype pair containing this known haplotypeand a new haplotype derived by subtracting the known haplotype from thepossible haplotype pair. Alternatively, the haplotype pair in anindividual may be predicted from the individual's genotype for that geneusing reported methods (e.g., Clark et al., Mol. Biol. Evol. 7:1121-1122(1990) or WO 01/80156) or through a commercial haplotyping service suchas offered by Genaissance Pharmaceuticals, Inc. (New Haven, Conn.). Inrare cases, either no haplotypes in the reference population areconsistent with the possible haplotype pairs, or alternatively, multiplereference haplotype pairs are consistent with the possible haplotypepairs. In such cases, the individual is preferably haplotyped using adirect molecular haplotyping method such as, for example, CLASPERSystem™ technology (U.S. Pat. No. 5,866,404), SME, or allele-specificlong-range PCR (Michalotos-Beloin et al., supra).

Determination of the number of haplotypes present in the individual fromthe genotypes is illustrated here for haplotype (147) in Table 1. Table3 below shows the nine (3^(n), where each of n bi-allelic polymorphicsites may have one of three different genotypes present) genotypes thatmay be detected at PS2 and PS4, using both chromosomal copies from anindividual. Eight of the nine possible genotypes allow unambiguousdetermination of the number of copies of the haplotype (147) in Table 1present in the individual and therefore would allow unambiguousdetermination of whether the individual has an age of onset marker I oran age of onset marker II. However, an individual with the T/C G/Agenotype could possess one of the following genotype pairs: TG/CA,CA/TG, TA/CG, and CG/TA, and thus could have either one copy ofhaplotype (147) in Table 1 (TG/CA, CA/TG), or zero copies (TA/CG, CG/TA)of haplotype (147) in Table 1. For instances where there is ambiguity inthe haplotype pair underlying the determined genotype (i.e., when two ormore PSs are included in the haplotype), frequency information may beused to determine the most probable haplotype pair and therefore themost likely number of copies of the haplotype in the individual. If aparticular haplotype pair consistent with the genotype of the individualis more frequent in the reference population than other pairs consistentwith the genotype, then that haplotype pair with the highest frequencyis the most likely to be present in the individual. The copy number ofthe haplotype of interest in this haplotype pair can then be determinedby visual inspection of the alleles at the PS that comprise the age ofonset marker for each haplotype in the pair.

Alternatively, for the ambiguous genotypes, genotyping of one or moreadditional sites in LDLR may be performed to eliminate the ambiguity indeconvoluting the haplotype pairs underlying the genotype at theparticular PSs. The skilled artisan would recognize that alleles atthese one or more additional sites would need to have sufficient linkagewith the alleles in at least one of the possible haplotypes in the pairto permit unambiguous assignment of the haplotype pair. Although thisillustration has been directed to the particular instance of determiningthe number of copies of haplotype (147) in Table 1 present in anindividual, the process would be analogous for the other haplotypesshown in Table 1, or for the linked haplotypes or substitute haplotypesfor any of the haplotypes in Table 1. TABLE 3 Possible Copy Numbers ofHaplotype (147) in Table 1 Based on Genotypes at PS2 and PS4 Copy Numberof Haplotype (147) PS2 PS4 in Table 1 T/T G/G 2 T/T G/A 1 T/T A/A 0 T/CG/G 1 T/C G/A 1 or 0 T/C A/A 0 C/C G/G 0 C/C G/A 0 C/C A/A 0

The individual's genotype for the desired set of PS may be determinedusing a variety of methods well-known in the art. Such methods typicallyinclude isolating from the individual a genomic DNA sample comprisingboth copies of the gene or locus of interest, amplifying from the sampleone or more target regions containing the polymorphic sites to begenotyped, and detecting the nucleotide pair present at each PS ofinterest in the amplified target region(s). It is not necessary to usethe same procedure to determine the genotype for each PS of interest.

In addition, the identity of the allele(s) present at any of the novelPSs described herein may be indirectly determined by haplotyping orgenotyping another PS having an allele that is in linkage disequilibriumwith an allele of the PS that is of interest. PSs having an allele inlinkage disequilibrium with an allele of the presently disclosed PSs maybe located in regions of the gene or in other genomic regions notexamined herein. Detection of the allele(s) present at a PS, wherein theallele is in linkage disequilibrium with an allele of the novel PSsdescribed herein may be performed by, but is not limited to, any of theabove-mentioned methods for detecting the identity of the allele at aPS.

Alternatively, the presence in an individual of a haplotype or haplotypepair for a set of PSs comprising an age of onset marker may bedetermined by directly haplotyping at least one of the copies of theindividual's genomic region of interest, or suitable fragment thereof,using methods known in the art. Such direct haplotyping methodstypically involve treating a genomic nucleic acid sample isolated fromthe individual in a manner that produces a hemizygous DNA sample thatonly has one of the two “copies” of the individual's genomic regionwhich, as readily understood by the skilled artisan, may be the sameallele or different alleles, amplifying from the sample one or moretarget regions containing the PSs to be genotyped, and detecting thenucleotide present at each PS of interest in the amplified targetregion(s). The nucleic acid sample may be obtained using a variety ofmethods known in the art for preparing hemizygous DNA samples, whichinclude: targeted in vivo cloning (TIVC) in yeast as described in WO98/01573, U.S. Pat. No. 5,866,404, and U.S. Pat. No. 5,972,614;generating hemizygous DNA targets-using an allele specificoligonucleotide in combination with primer extension and exonucleasedegradation as described in U.S. Pat. No. 5,972,614; single moleculedilution (SMD) as described in Ruaaño et al., Proc. Natl. Acad. Sci.87:6296-6300 (1990); and allele specific PCR (Ruaaño et al., Nucl. AcidsRes. 17:8392 (1989); Ruaaño et al., Nucl. Acids Res. 19:6877-6882(1991); Michalatos-Beloin et al., supra).

As will be readily appreciated by those skilled in the art, anyindividual clone will typically only provide haplotype information onone of the two genomic copies present in an individual. If haplotypeinformation is desired for the individual's other copy, additionalclones will usually need to be examined. Typically, at least five clonesshould be examined to have more than a 90% probability of haplotypingboth copies of the genomic locus in an individual. In some cases,however, once the haplotype for one genomic allele is directlydetermined, the haplotype for the other allele may be inferred if theindividual has a known genotype for the PSs of interest or if thehaplotype frequency or haplotype pair frequency for the individual'spopulation group is known.

While direct haplotyping of both copies of the gene is preferablyperformed with each copy of the gene being placed in separatecontainers, it is also envisioned that direct haplotyping could beperformed in the same container if the two copies are labeled withdifferent tags, or are otherwise separately distinguishable oridentifiable. For example, if first and second copies of the gene arelabeled with different first and second fluorescent dyes, respectively,and an allele-specific oligonucleotide labeled with yet a thirddifferent fluorescent dye is used to assay the PS(s), then detecting acombination of the first and third dyes would identify the polymorphismin the first gene copy while detecting a combination of the second andthird dyes would identify the polymorphism in the second gene copy.

The nucleic acid sample used in the above indirect and directhaplotyping methods is typically isolated from a biological sample takenfrom the individual, such as a blood sample or tissue sample. Suitabletissue samples include whole blood, saliva, tears, urine, skin and hair.

The target region(s) containing the PS of interest may be amplifiedusing any oligonucleotide-directed amplification method, including butnot limited to polymerase chain reaction (PCR) (U.S. Pat. No.4,965,188), ligase chain reaction (LCR) (Barany et al., Proc. Natl.Acad. Sci. USA 88:189-193 (1991); WO 90/01069), and oligonucleotideligation assay (OLA) (Landegren et al., Science 241:1077-1080 (1988)).Other known nucleic acid amplification procedures may be used to amplifythe target region(s) including transcription-based amplification systems(U.S. Pat. No. 5,130,238; European Patent No. EP 329,822; U.S. Pat. No.5,169,766; WO 89/06700) and isothermal methods (Walker et al., Proc.Natl. Acad. Sci. USA 89:392-396 (1992)).

In both the direct and indirect haplotyping methods, the identity of anucleotide (or nucleotide pair) at a PS(s) in the amplified targetregion may be determined by sequencing the amplified region(s) usingconventional methods. If both copies of the gene are represented in theamplified target, it will be readily appreciated by the skilled artisanthat only one nucleotide will be detected at a PS in individuals who arehomozygous at that site, while two different nucleotides will bedetected if the individual is heterozygous for that site. Thepolymorphism may be identified directly, known as positive-typeidentification, or by inference, referred to as negative-typeidentification. For example, where a polymorphism is known to be guanineand cytosine in a reference population, a site may be positivelydetermined to be either guanine or cytosine for an individual homozygousat that site, or both guanine and cytosine, if the individual isheterozygous at that site. Alternatively, the site may be negativelydetermined to be not guanine (and thus cytosine/cytosine) or notcytosine (and thus guanine/guanine).

A PS in the target region may also be assayed before or afteramplification using one of several hybridization-based methods known inthe art. Typically, allele-specific oligonucleotides are utilized inperforming such methods. The allele-specific oligonucleotides may beused as differently labeled probe pairs, with one member of the pairshowing a perfect match to one variant of a target sequence and theother member showing a perfect match to a different variant. In someembodiments, more than one PS may be detected at once using a set ofallele-specific oligonucleotides or oligonucleotide pairs. Preferably,the members of the set have melting temperatures within 5° C., and morepreferably within 2° C., of each other when hybridizing to each of thepolymorphic sites being detected.

Hybridization of an allele-specific oligonucleotide to a targetpolynucleotide may be performed with both entities in solution, or suchhybridization may be performed when either the oligonucleotide or thetarget polynucleotide is covalently or noncovalently affixed to a solidsupport. Attachment may be mediated, for example, by antibody-antigeninteractions, poly-L-Lys, streptavidin or avidin-biotin, salt bridges,hydrophobic interactions, chemical linkages, UV cross-linking baking,etc. Allele-specific oligonucleotides may be synthesized directly on thesolid support or attached to the solid support subsequent to synthesis.Solid-supports suitable for use in detection methods of the inventioninclude substrates made of silicon, glass, plastic, paper and the like,which may be formed, for example, into wells (as in 96-well plates),slides, sheets, membranes, fibers, chips, dishes, and beads. The solidsupport may be treated, coated or derivatized to facilitate theimmobilization of the allele-specific oligonucleotide or target nucleicacid.

Detecting the nucleotide or nucleotide pair at a PS of interest may alsobe determined using a mismatch detection technique, including but notlimited to the RNase protection method using riboprobes (Winter et al.,Proc. Natl. Acad. Sci. USA 82:7575 (1985); Meyers et al., Science230:1242 (1985)) and proteins which recognize nucleotide mismatches,such as the E. coli mutS protein (Modrich, Ann. Rev. Genet. 25:229-53(1991)). Alternatively, variant alleles can be identified by singlestrand conformation polymorphism (SSCP) analysis (Orita et al., Genomics5:874-879 (1989); Humphries et al., in Molecular Diagnosis of GeneticDiseases, Elles, ed. (1996), pp. 321-340), or denaturing gradient gelelectrophoresis (DGGE) (Wartell et al., Nucl. Acids Res. 18:2699-2706(1990); Sheffield et al., Proc. Natl. Acad. Sci. USA 86:232-236 (1989)).

A polymerase-mediated primer extension method may also be used toidentify the polymorphism(s). Several such methods have been describedin the patent and scientific literature and include the “Genetic BitAnalysis” method (WO 92/15712) and the ligase/polymerase mediatedgenetic bit analysis (U.S. Pat. No. 5,679,524. Related methods aredisclosed in WO 91/02087, WO 90/09455, WO 95/17676, and U.S. Pat. Nos.5,302,509 and 5,945,283. Extended primers containing the complement ofthe polymorphism may be detected by mass spectrometry as described inU.S. Pat. No. 5,605,798. Another primer extension method isallele-specific PCR (Ruaaño et al., 1989, supra; Ruaaño et al., 1991,supra; WO 93/22456; Turki et al., J. Clin. Invest. 95:1635-1641 (1995)).In addition, multiple PSs may be investigated by simultaneouslyamplifying multiple regions of the nucleic acid using sets ofallele-specific primers as described in WO 89/10414.

The genotype or haplotype for the LDLR gene of an individual may also bedetermined by hybridization of a nucleic acid sample containing one orboth copies of the gene, mRNA, cDNA or fragment(s) thereof, to nucleicacid arrays and subarrays such as described in WO 95/112995. The arrayswould contain a battery of allele-specific oligonucleotides representingeach of the PSs to be included in the genotype or haplotype.

The invention also provides a kit for determining whether an individualhas an age of onset marker I or an age of onset marker II. The kitcomprises a set of one or more oligonucleotides designed for identifyingat least one of the alleles at each PS in a set of one or more PSs,wherein the set of one or more PSs comprises (1) PS2, PS4, and PS14; (2)PS2, PS4, and PS6; (3) PS2, PS4, PS7, and PS13; (4) PS2, PS3, PS4, andPS6; (5) PS2, PS4, and PS13; (6) PS2, PS4, PS5, and PS13; (7) PS2, PS4,PS6, and PS9; (8) PS2, PS3, PS4, and PS7; (9) PS2, PS4, PS8, and PS13;(10) PS2, PS4, PS11, and PS14; (11) PS2, PS4, PS9, and PS11; (12) PS2,PS4, PS6, and PS14; (13) PS2, PS4, PS7, and PS14; (14) PS2, PS4, PS7,and PS9; (15) PS2, PS4, and PS9; (16) PS2, PS4, PS5, and PS9; (17) PS2,PS4, PS5, and PS14; (18) PS2, PS4, PS8, and PS14; (19) PS2, PS4, PS8,and PS9; (20) PS1, PS2, PS4, and PS13; (21) PS2, PS4, PS6, and PS11;(22) PS2, PS4, PS6, and PS7; (23) PS2, PS4, PS7, and PS11; (24) PS2,PS4, PS12, and PS13; (25) PS2, PS4, PS5, and PS6; 26) PS1, PS2, PS4, andPS9; (27) PS1, PS2, PS4, and PS14; (28) PS2, PS4, and PS7; (29) PS2,PS4, PS6, and PS8; (30) PS2, PS4, PS5, and PS7; (31) PS2, PS4, PS12, andPS14; (32) PS2, PS4, PS9, and PS12; (33) PS2, PS4, PS7, and PS8; (34)PS1, PS2, PS4, and PS6; (35) PS2, PS3, PS4, and PS13; (36) PS1, PS2,PS4, and PS7; (37) PS2, PS4, PS13, and PS14; (38) PS2, PS4, PS9, andPS13; (39) PS2, PS4, PS6, and PS12; (40) PS2, PS4, PS7, and PS12; (41)PS2, PS3, PS4, and PS9; (42) PS2, PS3, PS4, and PS14; (43) PS2, PS4,PS9, and PS14; (44) PS2, PS4, PS1, and PS13; (45) PS2, PS4, PS6, andPS13; (46) PS1, PS2, and PS9; (47) PS1, PS2, PS3, and PS9; (48) PS1,PS2, PS9, and PS12; (49) PS2, PS4, and PS5; (50) PS2, PS4, PS5, and PS8;(51) PS2, PS4, PS5, and PS12; (52) PS2, PS3, PS4, and PS5; (53) PS2,PS4, PS5, and PS11; (54) PS1, PS2, PS4, and PS5; (55) PS4, PS9, PS12,and PS14; (56) PS4, PS9, PS12, and PS13; (57) PS4, PS9, and PS12; (58)PS4, PS6, PS9, and PS12; (59) PS4, PS5, PS6, and PS12; (60) PS4, PS9,PS11, and PS12; (61) PS4, PS7, PS9, and PS12; (62) PS3, PS4, PS9, andPS12; (63) PS4, PS8, PS9, and PS12; (64) PS1, PS4, PS9, and PS12; (65)PS4, PS5, PS9, and PS12; (66) PS1, PS4, PS5, and PS12; (67) PS4, PS5,and PS12; (68) PS4, PS5, PS8, and PS12; (69) PS3, PS4, PS5, and PS12;(70) PS4, PS5, PS11, and PS12; (71) PS1, PS2, PS4, and PS9; (72) PS1,PS2, PS9, and PS11; (73) PS4, PS9, and PS13; (74) PS4, PS9, PS11, andPS14; (75) PS4, PS6, PS9, and PS13; (76) PS4, PS5, PS6, and PS13; (77)PS4, PS9, PS11, and PS13; (78) PS4, PS7, PS9, and PS14; (79) PS4, PS8,PS9, and PS14; (80) PS3, PS4, PS9, and PS14; (81) PS4, PS7, PS9, andPS13; (82) PS4, PS9, PS13, and PS14; (83) PS4, PS8, PS9, and PS13; (84)PS3, PS4, PS9, and PS13; (85) PS4, PS9, and PS14; (86) PS4, PS5, PS9,and PS14; (87) PS4, PS6, PS9, and PS14; (88) PS4, PS5, PS9, and PS13;(89) PS4, PS5, PS6, and PS14; (90) PS4 and PS9; (91) PS4, PS5, PS7, andPS9; (92) PS4, PS5, and PS9; (93) PS3, PS4, and PS9; (94) PS3, PS4, PS7,and PS9; (95) PS4, PS7, PS8, and PS9; (96) PS4, PS8, and PS9; (97) PS4,PS6, PS9, and PS11; (98) PS4, PS5, PS6, and PS1; (99) PS4, PS5, PS6, andPS9; (100) PS4, PS6, PS8, and PS9; (101) PS4, PS5, PS6, and PS8; (102)PS4, PS5, PS9, and PS11; (103) PS3, PS4, PS9, and PS11; (104) PS4, PS8,PS9, and PS11; (105) PS3, PS4, PS5, and PS9; (106) PS4, PS5, PS8, andPS9; (107) PS3, PS4, PS8, and PS9; (108) PS4, PS9, and PS1; (109) PS4,PS7, and PS9; (110) PS3, PS4, PS6, and PS9; (111) PS3, PS4, PS5, andPS6; (112) PS4, PS6, PS7, and PS9; (113) PS4, PS6, and PS9; (114) PS4,PS5, PS6, and PS7; (115) PS4, PS5, and PS6; (116) PS4, PS7, PS9, andPS11; (117) PS4, PS5, PS12, and PS14; (118) PS4, PS5, PS12, and PS13;(119) PS4, PS5, PS7, and PS12; (120) PS1, PS4, PS9, and PS14; (121) PS1,PS4, PS9, and PS13; (122) PS1, PS2, and PS5; (123) PS1, PS2, PS5, andPS9; (124) PS1, PS2, PS3, and PS5; (125) PS1, PS2, PS5, and PS12; (126)PS1, PS4, and PS9; (127) PS1, PS3, PS4, and PS9; (128) PS1, PS4, PS9,and PS11; (129) PS1, PS4, PS7, and PS9; (130) PS1, PS4, PS5, and PS9;(131) PS1, PS4, PS5, and PS6; (132) PS1, PS4, PS6, and PS9; (133) PS1,PS4, PS8, and PS9; (134) PS1 and PS9; (135) PS1, PS3, PS9, and PS12;(136) PS1, PS9, and PS12; (137) PS1, PS3, and PS9; (138) PS4 and PS5;(139) PS3, PS4, and PS5; (140) PS3, PS4, PS5, and PS11; (141) PS4, PS5,and PS11; (142) PS3, PS4, PS5, and PS8; (143) PS4, PS5, and PS8; (144)PS4, PS5, PS8, and PS11; (145) PS1, PS5, PS8, and PS13; (146) PS1, PS5,PS8, and PS14; (147) PS2 and PS4; (148) PS2, PS4, PS81, and PS12; (149)PS1, PS2, PS4, and PS11; (150) PS2, PS4, and PS11; (151) PS2, PS4, PS8,and PS12; (152) PS2, PS4, and PS8; (153) PS2, PS3, PS4, and PS12; (154)PS2, PS3, and PS4; (155) PS1, PS2, PS3, and PS4; (156) PS1, PS2, PS4,and PS8; (157) PS2, PS4, PS8, and PS11; (158) PS1, PS2, PS4, and PS12;(159) PS1, PS2, and PS4; (160) PS2, PS4, and PS12; (161) PS2, PS3, PS4,and PS11; (162) PS2, PS3, PS4, and PS8; (163) PS2, PS4, and PS9; (164)PS2, PS4, PS9, and PS12; (165) PS2, PS3, PS4, and PS9; (166) PS2 andPS9; (167) PS2, PS9, and PS12; (168) PS2, PS3, and PS9; (169) PS2, PS3,PS9, and PS12; (170) PS1 and PS5; (171) PS1, PS5, PS9, and PS12; (172)PS1, PS3, PS5, and PS12; (173) PS1, PS3, PS5, and PS9; (174) PS1, PS5,and PS12; (175) PS1, PS5, and PS9; (176) PS1, PS3, and PS5; (177) PS1,PS4, and PS5; (178) PS1, PS3, PS4, and PS5; (179) PS1, PS4, PS5, andPS11; (180) PS1, PS4, PS5, and PS8; (181) PS4, PS5, and PS14; (182) PS4,PS5, and PS13; (183) PS4, PS5, PS11, and PS14; (184) PS4, PS5, PS7, andPS14; (185) PS4, PS5, PS8, and PS14; (186) PS4, PS5, PS11, and PS13;(187) PS4, PS5, PS7, and PS13; (188) PS4, PS5, PS8, and PS13; (189) PS3,PS4, PS5, and PS14; (190) PS4, PS5, PS13, and PS14; (191) PS3, PS4, PS5,and PS13; (192) PS1, PS2, PS4, and PS5; (193) PS4, PS5, and PS7; (194)PS3, PS4, PS5, and PS7; (195) PS4, PS5, PS7, and PS11; (196) PS4, PS5,PS7, and PS8; (197) PS1, PS8, PS9, and PS13; (198) PS1, PS8, PS9, andPS14; (199) PS1, PS2, PS5, and PS11; (200) PS1, PS4, and PS9; (201) PS1,PS4, PS9, and PS12; (202) PS1, PS3, PS4, and PS9; (203) PS9, PS12, andPS14; (204) PS9, PS12, and PS13; (205) PS6, PS9, PS12, and PS14; (206)PS5, PS6, PS12, and PS14; (207) PS9, PS11, PS12, and PS14; (208) PS3,PS9, PS12, and PS14; (209) PS5, PS9, PS12, and PS14; (210) PS8, PS9,PS12, and PS14; (211) PS7, PS9, PS12, and PS13; (212) PS1, PS9, PS12,and PS14; (213) PS6, PS9, PS12, and PS13; (214) PS5, PS6, PS12, andPS13; (215) PS9, PS11, PS12, and PS13; (216) PS9, PS12, PS13, and PS14;(217) PS5, PS9, PS12, and PS13; (218) PS3, PS9, PS12, and PS13; (219)PS8, PS9, PS12, and PS13; (220) PS7, PS9, PS12, and PS14; (221) PS1,PS9, PS12, and PS13; (222) PS1, PS9, and PS11; (223) PS1, PS9, PS11, andPS12; (224) PS1, PS3, PS9, and PS11; (225) PS9 and PS12; (226) PS6, PS9,PS11, and PS12; (227) PS1, PS9, and PS12; (228) PS1, PS7, PS9, and PS12;(229) PS5, PS6, PS11, and PS12; (230) PS5, PS6, PS8, and PS12; (231)PS6, PS7, PS9, and PS12; (232) PS5, PS9, PS11, and PS12; (233) PS3, PS9,PS11, and PS12; (234) PS8, PS9, PS11, and PS12; (235) PS5, PS8, PS9, andPS12; (236) PS1, PS6, PS9, and PS12; (237) PS1, PS5, PS6, and PS12;(238) PS3, PS7, PS9, and PS12; (239) PS1, PS9, PS11, and PS12; (240)PS1, PS5, PS9, and PS12; (241) PS1, PS8, PS9, and PS12; (242) PS7, PS9,and PS12; (243) PS5, PS6, PS9, and PS12; (244) PS3, PS6, PS9, and PS12;(245) PS6, PS8, PS9, and PS12; (246) PS3, PS5, PS6, and PS12; (247) PS3,PS5, PS9, and PS12; (248) PS3, PS8, PS9, and PS12; (249) PS6, PS9, andPS12; (250) PS5, PS6, PS7, and PS12; (251) PS5, PS6, and PS12; (252)PS7, PS9, PS11, and PS12; (253) PS9, PS11, and PS12; (254) PS5, PS7,PS9, and PS12; (255) PS5, PS9, and PS12; (256) PS1, PS3, PS9, and PS12;(257) PS3, PS9, and PS12; (258) PS7, PS8, PS9, and PS12; (259) PS8, PS9,and PS12; (260) PS1, PS4, PS5, and PS14; (261) PS1, PS4, PS5, and PS13;(262) PS1, PS4, PS5, and PS7; (263) PS2, PS4, PS9, and PS11; (264) PS1,PS5, and PS12; (265) PS5 and PS12; (266) PS1, PS5, PS11, and PS12; (267)PS3, PS5, and PS12; (268) PS1, PS3, PS5, and PS12; (269) PS5, PS8, andPS12; (270) PS1, PS5, PS8, and PS12; (271) PS5, PS8, PS11, and PS12;(272) PS3, PS5, PS11, and PS12; (273) PS5, PS11, and PS12; (274) PS3,PS5, PS8, and PS12; (275) PS2, PS9, and PS11; (276) PS2, PS9, PS11, andPS12; (277) PS2, PS3, PS9, and PS11; (278) PS1, PS4, and PS5; (279) PS1,PS4, PS5, and PS12; (280) PS1, PS4, PS5, and PS9; (281) PS1, PS3, PS4,and PS5; (282) PS5, PS8, and PS13; (283) PS3, PS5, PS8, and PS14; (284)PS5, PS8, PS9, and PS14; (285) PS5, PS8, PS13, and PS14; (286) PS3, PS5,PS8, and PS13; (287) PS5, PS8, PS12, and PS14; (288) PS5, PS8, and PS14;(289) PS5, PS8, PS9, and PS13; (290) PS5, PS8, PS12, and PS13; (291)PS2, PS5, PS8, and PS14; (292) PS2, PS5, PS8, and PS13; (293) PS5, PS8,PS11, and PS14; (294) PS5, PS8, PS11, and PS13; (295) PS1, PS5, andPS11; (296) PS1, PS5, PS1, and PS12; (297) PS1, PS5, PS9, and PS11;(298) PS1, PS3, PS5, and PS11; (299) PS9 and PS14; (300) PS9 and PS13;(301) PS5, PS6, PS7, and PS14; (302) PS5, PS6, and PS14; (303) PS5, PS6,PS8, and PS14; (304) PS3, PS6, PS9, and PS13; (305) PS3, PS9, PS11, andPS13; (306) PS6, PS9, PS13, and PS14; (307) PS3, PS7, PS9, and PS13;(308) PS9, PS11, PS13, and PS14; (309) PS3, PS9, and PS13; (310) PS7,PS9, PS13, and PS14; (311) PS3, PS5, PS9, and PS13; (312) PS3, PS9,PS11, and PS14; (313) PS3, PS6, PS9, and PS14; (314) PS3, PS8, PS9, andPS13; (315) PS9, PS13, and PS14; (316) PS5, PS9, PS13, and PS14; (317)PS3, PS7, PS9, and PS14; (318) PS8, PS9, PS13, and PS14; (319) PS3, PS9,and PS14; (320) PS6, PS9, PS11, and PS13; (321) PS3, PS5, PS9, and PS14;(322) PS3, PS8, PS9, and PS14; (323) PS7, PS9, PS11, and PS13; (324)PS6, PS7, PS9, and PS13; (325) PS3, PS5, PS6, and PS13; (326) PS6, PS9,and PS13; (327) PS9, PS1, and PS13; (328) PS5, PS9, PS11, and PS13;(329) PS5, PS6, PS13, and PS14; (330) PS5, PS6, PS9, and PS13; (331)PS6, PS9, PS11, and PS14; (332) PS7, PS9, and PS13; (333) PS8, PS9,PS11, and PS13; (334) PS6, PS8, PS9, and PS13; (335) PS5, PS7, PS9, andPS13; (336) PS7, PS8, PS9, and PS13; (337) PS7, PS9, PS11, and PS14;(338) PS6, PS7, PS9, and PS14, (339) PS3, PS5, PS6, and PS14; (340) PS5,PS9, and PS13; (341) PS6, PS9, and PS14; (342) PS8, PS9, and PS13; (343)PS5, PS8, PS9, and PS13; (344) PS9, PS11, and PS14; (345) PS5, PS9,PS11, and PS14; (346) PS5, PS6, PS9, and PS14; (347) PS7, PS9, and PS14;(348) PS8, PS9, PS11, and PS14; (349) PS6, PS8, PS9, and PS14; (350)PS5, PS7, PS9, and PS14; (351) PS5, PS6, PS11, and PS13; (352) PS7, PS8,PS9, and PS14; (353) PS5, PS6, PS7, and PS13; (354) PS5, PS9, and PS14;(355) PS8, PS9, and PS14; (356) PS5, PS8, PS9, and PS14; (357) PS5, PS6,and PS13; (358) PS5, PS6, PS8, and PS13; (359) PS5, PS6, PS11, and PS14;(360) PS3, PS9, PS13, and PS14; (361) PS9; (362) PS6, PS8, PS9, andPS11; (363) PS5, PS7, PS9, and PS11; (364) PS5, PS6, PS7, and PS9; (365)PS6 and PS9; (366) PS7, PS8, PS9, and PS11; (367) PS6, PS7, PS8, andPS9; (368) PS3, PS5, PS6, and PS8; (369) PS9 and PS11; (370) PS5, PS6,and PS9; (371) PS5, PS9, and PS11; (372) PS7 and PS9; (373) PS6, PS8,and PS9; (374) PS8, PS9, and PS11; (375) PS5, PS7, and PS9; (376) PS5,PS8, PS9, and PS11; (377) PS5, PS6, PS8, and PS9; (378) PS7, PS8, andPS9; (379) PS5 and PS9; (380) PS5, PS7, PS8, and PS9; (381) PS8 and PS9;(382) PS5, PS8, and PS9; (383) PS5, PS6, PS7, and PS11; (384) PS5, PS6,and PS11; (385) PS5, PS6, and PS7; (386) PS5, PS6, PS8, and PS11; (387)PS5 and PS6; (388) PS5, PS6, PS7, and PS8; (389) PS5, PS6, and PS8;(390) PS3, PS6, PS9, and PS11; (391) PS3, PS6, PS7, and PS9; (392) PS3,PS7, PS9, and PS11; (393) PS3, PS6, and PS9; (394) PS3, PS9, and PS11;(395) PS3, PS5, PS6, and PS9; (396) PS3, PS5, PS9, and PS11; (397) PS3,PS6, PS8, and PS9; (398) PS3, PS7, and PS9; (399) PS3, PS8, PS9, andPS11; (400) PS3, PS5, PS7, and PS9; (401) PS3 and PS9; (402) PS3, PS7,PS8, and PS9; (403) PS3, PS5, and PS9; (404) PS3, PS8, and PS9; (405)PS3, PS5, PS8, and PS9; (406) PS6, PS7, PS9, and PS11; (407) PS3, PS5,PS6, and PS11; (408) PS6, PS9, and PS11; (409) PS3, PS5, PS6, and PS7;(410) PS5, PS6, PS9, and PS11; (411) PS3, PS5, and PS6; (412) PS6, PS7,and PS9; (413) PS7, PS9, and PS11; (414) PS9; (415) PS3, PS9, and PS12;(416) PS9 and PS12; (417) PS3 and PS9; (418) PS5, PS7, PS12, and PS14;(419) PS5, PS12, and PS13; (420) PS5, PS7, PS12, and PS13; (421) PS5,PS12, PS13, and PS14; (422) PS5, PS8, PS12, and PS13; (423) PS3, PS5,PS12, and PS13; (424) PS5, PS12, and PS14; (425) PS1, PS5, PS12, andPS14; (426) PS5, PS11, PS12, and PS14; (427) PS1, PS5, PS12, and PS13;(428) PS5, PS11, PS12, and PS13; (429) PS5, PS8, PS12, and PS14; (430)PS3, PS5, PS12, and PS14; (431) PS1, PS4, PS9, and PS11; (432) PS8, PS9,and PS13; (433) PS8, PS9, PS11, and PS14; (434) PS3, PS8, PS9, and PS14;(435) PS8, PS9, PS11, and PS13; (436) PS3, PS8, PS9, and PS13; (437)PS8, PS9, PS13, and PS14; (438) PS2, PS8, PS9, and PS14; (439) PS8, PS9,PS12, and PS14; (440) PS8, PS9, and PS14; (441) PS2, PS8, PS9, and PS13;(442) PS8, PS9, PS12, and PS13; (443) PS4 and PS9; (444) PS3, PS4, PS9,and PS12; (445) PS4, PS9, and PS12; (446) PS3, PS4, and PS9; (447) PS1,PS5, PS7, and PS12; (448) PS5, PS7, and PS12; (449) PS3, PS5, PS7, andPS12; (450) PS5, PS7, PS11, and PS12; (451) PS5, PS7, PS8, and PS12;(452) PS2 and PS5; (453) PS2, PS3, PS5, and PS9; (454) PS2, PS5, andPS12; (455) PS2, PS5, and PS9; (456) PS2, PS3, and PS5; (457) PS2, PS5,PS9, and PS12; (458) PS2, PS3, PS5, and PS12; (459) PS2, PS4, and PS5;(460) PS2, PS4, PS5, and PS12; (461) PS2, PS4, PS5, and PS9; (462) PS2,PS3, PS4, and PS5; (463) PS9, PS11, and PS14; (464) PS9, PS11, and PS13;(465) PS3, PS9, PS11, and PS14; (466) PS9, PS11, PS13, and PS14; (467)PS3, PS9, PS11, and PS13; (468) PS9, PS11, PS12, and PS14; (469) PS2,PS9, PS11, and PS14; (470) PS9, PS1, PS12, and PS13; (471) PS2, PS9,PS1, and PS13; (472) PS1, PS9, and PS14; (473) PS1, PS9, and PS13; (474)PS1, PS8, PS9, and PS13; (475) PS1, PS3, PS9, and PS14; (476) PS1, PS5,PS9, and PS14; (477) PS1, PS9, PS13, and PS14; (478) PS1, PS3, PS9, andPS13; (479) PS1, PS6, PS9, and PS14; (480) PS1, PS5, PS9, and PS13;(481) PS1, PS5, PS6, and PS14; (482) PS1, PS6, PS9, and PS13; (483) PS1,PS5, PS6, and PS13; (484) PS1, PS9, PS11, and PS14; (485) PS1, PS7, PS9,and PS14; (486) PS1, PS8, PS9, and PS14; (487) PS1, PS9, PS11, and PS13;(488) PS1, PS7, PS9, and PS13; (489) PS1 and PS9; (490) PS1, PS6, PS7,and PS9; (491) PS1, PS5, PS9, and PS11; (492) PS1, PS8, PS9, and PS11;(493) PS1, PS5, PS8, and PS9; (494) PS1, PS3, PS7, and PS9; (495) PS1,PS3, and PS9; (496) PS1, PS7, and PS9; (497) PS1, PS5, PS6, and PS9;(498) PS1, PS3, PS6, and PS9; (499) PS1, PS6, PS8, and PS9; (500) PS1,PS3, PS5, and PS6; (501) PS1, PS5, PS6, and PS8; (502) PS1, PS3, PS9,and PS11; (503) PS1, PS3, PS5, and PS9; (504) PS1, PS3, PS8, and PS9;(505) PS1, PS6, and PS9; (506) PS1, PS5, and PS6; (507) PS1, PS5, PS6,and PS7; (508) PS1, PS7, PS9, and PS11; (509) PS1, PS9, and PS11; (510)PS1, PS5, PS7, and PS9; (511) PS1, PS5, and PS9; (512) PS1, PS7, PS8,and PS9; (513) PS1, PS8, and PS9; (514) PS1, PS6, PS9, and PS1; (515)PS1, PS5, PS6, and PS11; (516) PS2 and PS14; (517) PS2, PS5, and PS9;(518) PS2, PS3, PS6, and PS7; (519) PS2, PS3, PS7, and PS13; (520) PS1,PS2, and PS14; (521) PS1, PS2, PS7, and PS8; (522) PS2, PS7, PS8, andPS9; (523) PS2, PS9, and PS14; (524) PS2, PS3, PS11, and PS14; (525)PS2, PS3, PS12, and PS14; (526) PS1, PS2, PS6, and PS11; (527) PS1, PS2,PS11, and PS13; (528) PS2, PS9, PS11, and PS13; (529) PS2, PS6, PS9, andPS11; (530) PS1, PS2, PS6, and PS12; (531) PS1, PS2, PS12, and PS13;(532) PS2, PS9, PS12, and PS13; (533) PS2, PS6, PS9, and PS12; (534)PS2, PS3, PS8, and PS9; (535) PS2, PS7, and PS11; (536) PS2, PS5, andPS14; (537) PS2, PS7, and PS12; (538) PS2, PS5, PS11, and PS13; (539)PS2, PS5, PS12, and PS13; (540) PS2, PS6, PS8, and PS13; (541) PS2 andPS9; (542) PS2, PS3, PS6, and PS13; (543) PS1, PS2, PS8, and PS13; (544)PS1, PS2, PS3, and PS7; (545) PS2, PS3, PS7, and PS9; (546) PS1, PS2,PS9, and PS11; (547) PS1, PS2, PS9, and PS12; (548) PS2, PS5, PS7, andPS8; (549) PS2, PS5, PS6, and PS11; (550) PS2, PS7, PS8, and PS14; (551)PS2, PS5, PS6, and PS12; (552) PS2, PS6, PS7, and PS13; (553) PS2, PS3,PS5, and PS7; (554) PS2, PS11, PS13, and PS14; (555) PS2, PS6, PS11, andPS14; (556) PS2, PS12, PS13, and PS14; (557) PS2, PS6, PS12, and PS14;(558) PS1, PS2, PS7, and PS13; (559) PS2, PS3, PS8, and PS14; (560) PS1,PS2, PS6, and PS8; (561) PS2, PS8, PS9, and PS13; (562) PS2, PS6, PS8,and PS9; (563) PS1, PS2, PS3, and PS6; (564) PS1, PS2, PS3, and PS13;(565) PS2, PS3, PS9, and PS13; (566) PS2, PS7, and PS8; (567) PS2, PS6,and PS11; (568) PS2, PS11, and PS13; (569) PS2, PS5, PS6, and PS8; (570)PS2, PS5, PS8, and PS13; (571) PS2, PS12, and PS13; (572) PS2, PS6, andPS12; (573) PS2, PS8, PS13, and PS14; (574) PS2, PS3, PS7, and PS14;(575) PS1, PS2, PS6, and PS7; (576) PS2, PS5, PS9, and PS11; (577) PS2,PS7, PS9, and PS13; (578) PS2, PS5, PS9, and PS12; (579) PS2, PS6, PS7,and PS9; (580) PS1, PS2, PS11, and PS14; (581) PS2, PS9, PS11, and PS14;(582) PS1, PS2, PS12, and PS14; (583) PS2, PS9, PS12, and PS14; (584)PS2, PS3, PS6, and PS9; (585) PS1, PS2, PS8, and PS9; (586) PS2, PS5,PS6, and PS7; (587) PS2, PS5, PS7, and PS13; (588) PS1, PS2, PS3, andPS9; (589) PS2, PS5, PS11, and PS14; (590) PS2, PS8, and PS13; (591)PS2, PS7, PS11, and PS12; (592) PS2, PS3, and PS7; (593) PS2, PS7, PS13,and PS14; (594) PS2, PS5, PS12, and PS14; (595) PS2, PS6, PS8, and PS14;(596) PS2, PS3, PS5, and PS13; (597) PS2, PS3, PS5, and PS6; (598) PS2,PS9, and PS11; (599) PS2, PS5, PS8, and PS9; (600) PS2, PS9, and PS12;(601) PS2, PS3, PS6, and PS14; (602) PS2, PS3, PS13, and PS14; (603)PS1, PS2, PS8, and PS14; (604) PS1, PS2, PS6, and PS13; (605) PS2, PS6,PS9, and PS13; (606) PS1, PS2, PS7, and PS9; (607) PS2, PS7, and PS13;(608) PS2, PS6, and PS8; (609) PS2, PS6, PS7, and PS14; (610) PS1, PS2,PS5, and PS7; (611) PS2, PS5, PS7, and PS9; (612) PS2, PS3, and PS6;(613) PS2, PS3, and PS13; (614) PS1, PS2, PS7, and PS14; (615) PS2, PS8,PS9, and PS14; (616) PS2, PS3, PS5, and PS9; (617) PS1, PS2, PS3, andPS14; (618) PS2, PS3, PS9, and PS14; (619) PS1, PS2, PS9, and PS13;(620) PS1, PS2, PS6, and PS9; (621) PS2, PS6, and PS7; (622) PS2, PS7,PS8, and PS11; (623) PS2, PS11, and PS14; (624) PS2, PS5, PS8, and PS14;(625) PS2, PS7, PS8, and PS12; (626) PS2, PS5, PS6, and PS13; (627) PS2,PS12, and PS14; (628) PS1, PS2, and PS7; (629) PS2, PS11, PS12, andPS13; (630) PS2, PS6, PS11, and PS12; (631) PS2, PS6, PS13, and PS14;(632) PS2, PS8, and PS9; (633) PS2, PS7, PS9, and PS14; (634) PS1, PS2,PS5, and PS13; (635) PS2, PS3, and PS9; (636) PS2, PS5, PS7, and PS14;(637) PS2, PS8, and PS14; (638) PS2, PS6, and PS13; (639) PS2, PS8,PS11, and PS13; (640) PS2, PS7, and PS9; (641) PS2, PS3, PS7, and PS11;(642) PS2, PS8, PS12, and PS13; (643) PS2, PS3, PS5, and PS14; (644)PS2, PS3, PS7, and PS12; (645) PS1, PS2, PS5, and PS6; (646) PS2, PS5,PS6, and PS9; (647) PS2, PS5, PS9, and PS13; (648) PS1, PS2, PS6, andPS14; (649) PS1, PS2, PS13, and PS14; (650) PS2, PS9, PS81, and PS12;(651) PS2, PS9, PS13, and PS14; (652) PS2, PS6, PS9, and PS14; (653)PS2, PS5, and PS7; (654) PS2, PS7, and PS14; (655) PS2, PS7, PS11, andPS13; (656) PS2, PS5, PS13, and PS14; (657) PS2, PS7, PS12, and PS13;(658) PS2, PS6, PS8, and PS11; (659) PS2, PS6, PS8, and PS12; (660) PS2,PS3, PS7, and PS8; (661) PS2, PS3, and PS14; (662) PS1, PS2, and PS6;(663) PS1, PS2, and PS13; (664) PS2, PS6, and PS9; (665) PS2, PS9, andPS13; (666) PS2, PS3, PS6, and PS11; (667) PS2, PS3, PS81, and PS13;(668) PS2, PS3, PS12, and PS13; (669) PS2, PS3, PS6, and PS12; (670)PS1, PS2, PS5, and PS9; (671) PS2 and PS7; (672) PS1, PS2, PS9, andPS14; (673) PS2, PS5, and PS13; (674) PS2, PS6, PS7, and PS11; (675)PS2, PS5, PS6, and PS14; (676) PS2, PS6, PS7, and PS12; (677) PS2, PS11,PS12, and PS14; (678) PS1, PS2, PS7, and PS11; (679) PS1, PS2, PS5, andPS14; (680) PS1, PS2, PS7, and PS12; (681) PS2, PS8, PS9, and PS11;(682) PS2, PS8, PS9, and PS12; (683) PS1, PS2, and PS9; (684) PS2, PS3,PS9, and PS11; (685) PS2, PS3, PS9, and PS12; (686) PS2, PS5, and PS6;(687) PS2, PS7, PS8, and PS13; (688) PS2, PS6, and PS14; (689) PS2,PS13, and PS14; (690) PS2, PS6, PS7, and PS8; (691) PS2, PS8, PS1, andPS14; (692) PS2, PS6, PS81, and PS13; (693) PS2, PS8, PS12, and PS14;(694) PS2, PS6, PS12, and PS13; (695) PS2, PS7, PS9, and PS11; (696)PS2, PS5, PS9, and PS14; (697) PS2, PS7, PS9, and PS12; (698) PS2, PS3,PS6, and PS8; (699) PS2, PS3, PS8, and PS13; (700) PS2 and PS13; (701)PS2, PS5, PS7, and PS11; (702) PS2, PS5, PS7, and PS12; (703) PS2, PS7,PS11, and PS14; (704) PS2, PS7, PS12, and PS14; (705) PS5; (706) PS5,PS8, and PS11; (707) PS3 and PS5; (708) PS3, PS5, and PS11; (709) PS5and PS11; (710) PS3, PS5, and PS8; (711) PS3, PS5, PS8, and PS11; (712)PS5 and PS8; (713) PS5; (714) PS3, PS5, PS9, and PS12; (715) PS5, PS9,and PS12; (716) PS3, PS5, and PS12; (717) PS3, PS5, and PS9; (718) PS5and PS12; (719) PS5 and PS9; (720) PS3 and PS5; (721) PS9 and PS13;(722) PS2, PS9, and PS13; (723) PS3, PS9, PS12, and PS14; (724) PS9,PS12, PS13, and PS14; (725) PS2, PS9, PS12, and PS14; (726) PS3, PS9,PS13, and PS14; (727) PS9, PS12, and PS14; (728) PS2, PS3, PS9, andPS14; (729) PS2, PS9, PS13, and PS14; (730) PS3, PS9, and PS14; (731)PS9, PS13, and PS14; (732) PS2, PS9, and PS14; (733) PS9 and PS14; (734)PS3, PS9, PS12, and PS13; (735) PS2, PS9, PS12, and PS13; (736) PS9,PS12, and PS13; (737) PS2, PS3, PS9, and PS13; (738) PS3, PS9, and PS13;(739) PS1, PS4, PS5, and PS11; (740) PS4, PS8, PS9, and PS13; (741) PS4,PS8, PS9, and PS14; (742) PS2 and PS5; (743) PS2, PS5, PS8, and PS11;(744) PS2, PS3, PS5, and PS11; (745) PS1, PS2, PS5, and PS12; (746) PS2,PS5, and PS12; (747) PS1, PS2, and PS5; (748) PS2, PS3, PS5, and PS8;(749) PS2, PS5, PS11, and PS12; (750) PS1, PS2, PS5, and PS11; (751)PS2, PS5, and PS11; (752) PS2, PS5, PS8, and PS12; (753) PS2, PS3, PS5,and PS12; (754) PS2, PS3, and PS5; (755) PS2, PS5, and PS8; (756) PS1,PS2, PS5, and PS8; (757) PS1, PS2, PS3, and PS5; (758) PS4 and PS5;(759) PS4, PS5, PS9, and PS12; (760) PS3, PS4, PS5, and PS12; (761) PS3,PS4, PS5, and PS9; (762) PS4, PS5, and PS12; (763) PS4, PS5, and PS9;(764) PS3, PS4, and PS5; (765) a set of one or more PSs in a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, or (766) a set ofone or more PSs in a substitute haplotype for any of haplotypes(1)-(764) in Table 1. Preferably, the kit comprises a set of one or moreoligonucleotides designed for identifying at least one of the alleles ateach PS in a set of one or more PSs, wherein the set of one or more PSsis any of (1) PS2, PS4, and PS14; (2) PS2, PS4, and PS6; (3) PS2, PS4,PS7, and PS13; (4) PS2, PS3, PS4, and PS6; (5) PS2, PS4, and PS13; (6)PS2, PS4, PS5, and PS13; (7) PS2, PS4, PS6, and PS9; (8) PS2, PS3, PS4,and PS7; (9) PS2, PS4, PS8, and PS13; (10) PS2, PS4, PS11, and PS14;(11) PS2, PS4, PS9, and PS11; (12) PS2, PS4, PS6, and PS14; (13) PS2,PS4, PS7, and PS14; (14) PS2, PS4, PS7, and PS9; (15) PS2, PS4, and PS9;(16) PS2, PS4, PS5, and PS9; (17) PS2, PS4, PS5, and PS14; (18) PS2,PS4, PS8, and PS14; (19) PS2, PS4, PS8, and PS9; (20) PS1, PS2, PS4, andPS13; (21) PS2, PS4, PS6, and PS11; (22) PS2, PS4, PS6, and PS7; (23)PS2, PS4, PS7, and PS11; (24) PS2, PS4, PS12, and PS13; (25) PS2, PS4,PS5, and PS6; 26) PS1, PS2, PS4, and PS9; (27) PS1, PS2, PS4, and PS14;(28) PS2, PS4, and PS7; (29) PS2, PS4, PS6, and PS8; (30) PS2, PS4, PS5,and PS7; (31) PS2, PS4, PS12, and PS14; (32) PS2, PS4, PS9, and PS12;(33) PS2, PS4, PS7, and PS8; (34) PS1, PS2, PS4, and PS6; (35) PS2, PS3,PS4, and PS13; (36) PS1, PS2, PS4, and PS7; (37) PS2, PS4, PS13, andPS14; (38) PS2, PS4, PS9, and PS13; (39) PS2, PS4, PS6, and PS12; (40)PS2, PS4, PS7, and PS12; (41) PS2, PS3, PS4, and PS9; (42) PS2, PS3,PS4, and PS14; (43) PS2, PS4, PS9, and PS14; (44) PS2, PS4, PS11, andPS13; (45) PS2, PS4, PS6, and PS13; (46) PS1, PS2, and PS9; (47) PS1,PS2, PS3, and PS9; (48) PS1, PS2, PS9, and PS12; (49) PS2, PS4, and PS5;(50) PS2, PS4, PS5, and PS8; (51) PS2, PS4, PS5, and PS12; (52) PS2,PS3, PS4, and PS5; (53) PS2, PS4, PS5, and PS11; (54) PS1, PS2, PS4, andPS5; (55) PS4, PS9, PS12, and PS14; (56) PS4, PS9, PS12, and PS13; (57)PS4, PS9, and PS12; (58) PS4, PS6, PS9, and PS12; (59) PS4, PS5, PS6,and PS12; (60) PS4, PS9, PS11, and PS12; (61) PS4, PS7, PS9, and PS12;(62) PS3, PS4, PS9, and PS12; (63) PS4, PS8, PS9, and PS12; (64) PS1,PS4, PS9, and PS12; (65) PS4, PS5, PS9, and PS12; (66) PS1, PS4, PS5,and PS12; (67) PS4, PS5, and PS12; (68) PS4, PS5, PS8, and PS12; (69)PS3, PS4, PS5, and PS12; (70) PS4, PS5, PS11, and PS12; (71) PS1, PS2,PS4, and PS9; (72) PS1, PS2, PS9, and PS11; (73) PS4, PS9, and PS13;(74) PS4, PS9, PS11, and PS14; (75) PS4, PS6, PS9, and PS13; (76) PS4,PS5, PS6, and PS13; (77) PS4, PS9, PS11, and PS13; (78) PS4, PS7, PS9,and PS14; (79) PS4, PS8, PS9, and PS14; (80) PS3, PS4, PS9, and PS14;(81) PS4, PS7, PS9, and PS13; (82) PS4, PS9, PS13, and PS14; (83) PS4,PS8, PS9, and PS13; (84) PS3, PS4, PS9, and PS13; (85) PS4, PS9, andPS14; (86) PS4, PS5, PS9, and PS14; (87) PS4, PS6, PS9, and PS14; (88)PS4, PS5, PS9, and PS13; (89) PS4, PS5, PS6, and PS14; (90) PS4 and PS9;(91) PS4, PS5, PS7, and PS9; (92) PS4, PS5, and PS9; (93) PS3, PS4, andPS9; (94) PS3, PS4, PS7, and PS9; (95) PS4, PS7, PS8, and PS9; (96) PS4,PS8, and PS9; (97) PS4, PS6, PS9, and PS11; (98) PS4, PS5, PS6, andPS11; (99) PS4, PS5, PS6, and PS9; (100) PS4, PS6, PS8, and PS9; (101)PS4, PS5, PS6, and PS8; (102) PS4, PS5, PS9, and PS11; (103) PS3, PS4,PS9, and PS11; (104) PS4, PS8, PS9, and PS11; (105) PS3, PS4, PS5, andPS9; (106) PS4, PS5, PS8, and PS9; (107) PS3, PS4, PS8, and PS9; (108)PS4, PS9, and PS11; (109) PS4, PS7, and PS9; (110) PS3, PS4, PS6, andPS9; (11) PS3, PS4, PS5, and PS6; (112) PS4, PS6, PS7, and PS9; (113)PS4, PS6, and PS9; (114) PS4, PS5, PS6, and PS7; (115) PS4, PS5, andPS6; (116) PS4, PS7, PS9, and PS11; (117) PS4, PS5, PS12, and PS14;(118) PS4, PS5, PS12, and PS13; (119) PS4, PS5, PS7, and PS12; (120)PS1, PS4, PS9, and PS14; (121) PS1, PS4, PS9, and PS13; (122) PS1, PS2,and PS5; (123) PS1, PS2, PS5, and PS9; (124) PS1, PS2, PS3, and PS5;(125) PS1, PS2, PS5, and PS12; (126) PS1, PS4, and PS9; (127) PS1, PS3,PS4, and PS9; (128) PS1, PS4, PS9, and PS11; (129) PS1, PS4, PS7, andPS9; (130) PS1, PS4, PS5, and PS9; (131) PS1, PS4, PS5, and PS6; (132)PS1, PS4, PS6, and PS9; (133) PS1, PS4, PS8, and PS9; (134) PS1 and PS9;(135) PS1, PS3, PS9, and PS12; (136) PS1, PS9, and PS12; (137) PS1, PS3,and PS9; (138) PS4 and PS5; (139) PS3, PS4, and PS5; (140) PS3, PS4,PS5, and PS11; (141) PS4, PS5, and PS11; (142) PS3, PS4, PS5, and PS8;(143) PS4, PS5, and PS8; (144) PS4, PS5, PS8, and PS11; (145) PS1, PS5,PS8, and PS13; (146) PS1, PS5, PS8, and PS14; (147) PS2 and PS4; (148)PS2, PS4, PS11, and PS12; (149) PS1, PS2, PS4, and PS11; (150) PS2, PS4,and PS11; (151) PS2, PS4, PS8, and PS12; (152) PS2, PS4, and PS8; (153)PS2, PS3, PS4, and PS12; (154) PS2, PS3, and PS4; (155) PS1, PS2, PS3,and PS4; (156) PS1, PS2, PS4, and PS8; (157) PS2, PS4, PS8, and PS11;(158) PS1, PS2, PS4, and PS12; (159) PS1, PS2, and PS4; (160) PS2, PS4,and PS12; (161) PS2, PS3, PS4, and PS11; (162) PS2, PS3, PS4, and PS8;(163) PS2, PS4, and PS9; (164) PS2, PS4, PS9, and PS12; (165) PS2, PS3,PS4, and PS9; (166) PS2 and PS9; (167) PS2, PS9, and PS12; (168) PS2,PS3, and PS9; (169) PS2, PS3, PS9, and PS12; (170) PS1 and PS5; (171)PS1, PS5, PS9, and PS12; (172) PS1, PS3, PS5, and PS12; (173) PS1, PS3,PS5, and PS9; (174) PS1, PS5, and PS12; (175) PS1, PS5, and PS9; (176)PS1, PS3, and PS5; (177) PS1, PS4, and PS5; (178) PS1, PS3, PS4, andPS5; (179) PS1, PS4, PS5, and PS11; (180) PS1, PS4, PS5, and PS8; (181)PS4, PS5, and PS14; (182) PS4, PS5, and PS13; (183) PS4, PS5, PS11, andPS14; (184) PS4, PS5, PS7, and PS14; (185) PS4, PS5, PS8, and PS14;(186) PS4, PS5, PS11, and PS13; (187) PS4, PS5, PS7, and PS13; (188)PS4, PS5, PS8, and PS13; (189) PS3, PS4, PS5, and PS14; (190) PS4, PS5,PS13, and PS14; (191) PS3, PS4, PS5, and PS13; (192) PS1, PS2, PS4, andPS5; (193) PS4, PS5, and PS7; (194) PS3, PS4, PS5, and PS7; (195) PS4,PS5, PS7, and PS11; (196) PS4, PS5, PS7, and PS8; (197) PS1, PS8, PS9,and PS13; (198) PS1, PS8, PS9, and PS14; (199) PS1, PS2, PS5, and PS11;(200) PS1, PS4, and PS9; (201) PS1, PS4, PS9, and PS12; (202) PS1, PS3,PS4, and PS9; (203) PS9, PS12, and PS14; (204) PS9, PS12, and PS13;(205) PS6, PS9, PS12, and PS14; (206) PS5, PS6, PS12, and PS14; (207)PS9, PS11, PS12, and PS14; (208) PS3, PS9, PS12, and PS14; (209) PS5,PS9, PS12, and PS14; (210) PS8, PS9, PS12, and PS14; (211) PS7, PS9,PS12, and PS13; (212) PS1, PS9, PS12, and PS14; (213) PS6, PS9, PS12,and PS13; (214) PS5, PS6, PS12, and PS13; (215) PS9, PS11, PS12, andPS13; (216) PS9, PS12, PS13, and PS14; (217) PS5, PS9, PS12, and PS13;(218) PS3, PS9, PS12, and PS13; (219) PS8, PS9, PS12, and PS13; (220)PS7, PS9, PS12, and PS14; (221) PS1, PS9, PS12, and PS13; (222) PS1,PS9, and PS11; (223) PS1, PS9, PS11, and PS12; (224) PS1, PS3, PS9, andPS11; (225) PS9 and PS12; (226) PS6, PS9, PS11, and PS12; (227) PS1,PS9, and PS12; (228) PS1, PS7, PS9, and PS12; (229) PS5, PS6, PS11, andPS12; (230) PS5, PS6, PS8, and PS12; (231) PS6, PS7, PS9, and PS12;(232) PS5, PS9, PS11, and PS12; (233) PS3, PS9, PS11, and PS12; (234)PS8, PS9, PS11, and PS12; (235) PS5, PS8, PS9, and PS12; (236) PS1, PS6,PS9, and PS12; (237) PS1, PS5, PS6, and PS12; (238) PS3, PS7, PS9, andPS12; (239) PS1, PS9, PS11, and PS12; (240) PS1, PS5, PS9, and PS12;(241) PS1, PS8, PS9, and PS12; (242) PS7, PS9, and PS12; (243) PS5, PS6,PS9, and PS12; (244) PS3, PS6, PS9, and PS12; (245) PS6, PS8, PS9, andPS12; (246) PS3, PS5, PS6, and PS12; (247) PS3, PS5, PS9, and PS12;(248) PS3, PS8, PS9, and PS12; (249) PS6, PS9, and PS12; (250) PS5, PS6,PS7, and PS12; (251) PS5, PS6, and PS12; (252) PS7, PS9, PS11, and PS12;(253) PS9, PS11, and PS12; (254) PS5, PS7, PS9, and PS12; (255) PS5,PS9, and PS12; (256) PS1, PS3, PS9, and PS12; (257) PS3, PS9, and PS12;(258) PS7, PS8, PS9, and PS12; (259) PS8, PS9, and PS12; (260) PS1, PS4,PS5, and PS14; (261) PS1, PS4, PS5, and PS13; (262) PS1, PS4, PS5, andPS7; (263) PS2, PS4, PS9, and PS1; (264) PS1, PS5, and PS12; (265) PS5and PS12; (266) PS1, PS5, PS1, and PS12; (267) PS3, PS5, and PS12; (268)PS1, PS3, PS5, and PS12; (269) PS5, PS8, and PS12; (270) PS1, PS5, PS8,and PS12; (271) PS5, PS8, PS11, and PS12; (272) PS3, PS5, PS11, andPS12; (273) PS5, PS11, and PS12; (274) PS3, PS5, PS8, and PS12; (275)PS2, PS9, and PS11; (276) PS2, PS9, PS11, and PS12; (277) PS2, PS3, PS9,and PS11; (278) PS1, PS4, and PS5; (279) PS1, PS4, PS5, and PS12; (280)PS1, PS4, PS5, and PS9; (281) PS1, PS3, PS4, and PS5; (282) PS5, PS8,and PS13; (283) PS3, PS5, PS8, and PS14; (284) PS5, PS8, PS9, and PS14;(285) PS5, PS8, PS13, and PS14; (286) PS3, PS5, PS8, and PS13; (287)PS5, PS8, PS12, and PS14; (288) PS5, PS8, and PS14; (289) PS5, PS8, PS9,and PS13; (290) PS5, PS8, PS12, and PS13; (291) PS2, PS5, PS8, and PS14;(292) PS2, PS5, PS8, and PS13; (293) PS5, PS8, PS11, and PS14; (294)PS5, PS8, PS11, and PS13; (295) PS1, PS5, and PS11; (296) PS1, PS5,PS11, and PS12; (297) PS1, PS5, PS9, and PS11; (298) PS1, PS3, PS5, andPS11; (299) PS9 and PS14; (300) PS9 and PS13; (301) PS5, PS6, PS7, andPS14; (302) PS5, PS6, and PS14; (303) PS5, PS6, PS8, and PS14; (304)PS3, PS6, PS9, and PS13; (305) PS3, PS9, PS11, and PS13; (306) PS6, PS9,PS13, and PS14; (307) PS3, PS7, PS9, and PS13; (308) PS9, PS11, PS13,and PS14; (309) PS3, PS9, and PS13; (310) PS7, PS9, PS13, and PS14;(311) PS3, PS5, PS9, and PS13; (312) PS3, PS9, PS11, and PS14; (313)PS3, PS6, PS9, and PS14; (314) PS3, PS8, PS9, and PS13; (315) PS9, PS13,and PS14; (316) PS5, PS9, PS13, and PS14; (317) PS3, PS7, PS9, and PS14;(318) PS8, PS9, PS13, and PS14; (319) PS3, PS9, and PS14; (320) PS6,PS9, PS11, and PS13; (321) PS3, PS5, PS9, and PS14; (322) PS3, PS8, PS9,and PS14; (323) PS7, PS9, PS1, and PS13; (324) PS6, PS7, PS9, and PS13;(325) PS3, PS5, PS6, and PS13; (326) PS6, PS9, and PS13; (327) PS9,PS11, and PS13; (328) PS5, PS9, PS11, and PS13; (329) PS5, PS6, PS13,and PS14; (330) PS5, PS6, PS9, and PS13; (331) PS6, PS9, PS11, and PS14;(332) PS7, PS9, and PS13; (333) PS8, PS9, PS11, and PS13; (334) PS6,PS8, PS9, and PS13; (335) PS5, PS7, PS9, and PS13; (336) PS7, PS8, PS9,and PS13; (337) PS7, PS9, PS11, and PS14; (338) PS6, PS7, PS9, and PS14;(339) PS3, PS5, PS6, and PS14; (340) PS5, PS9, and PS13; (341) PS6, PS9,and PS14; (342) PS8, PS9, and PS13; (343) PS5, PS8, PS9, and PS13; (344)PS9, PS11, and PS14; (345) PS5, PS9, PS1, and PS14; (346) PS5, PS6, PS9,and PS14; (347) PS7, PS9, and PS14; (348) PS8, PS9, PS11, and PS14;(349) PS6, PS8, PS9, and PS14; (350) PS5, PS7, PS9, and PS14; (351) PS5,PS6, PS11, and PS13; (352) PS7, PS8, PS9, and PS14; (353) PS5, PS6, PS7,and PS13; (354) PS5, PS9, and PS14; (355) PS8, PS9, and PS14; (356) PS5,PS8, PS9, and PS14; (357) PS5, PS6, and PS13; (358) PS5, PS6, PS8, andPS13; (359) PS5, PS6, PS11, and PS14; (360) PS3, PS9, PS13, and PS14;(361) PS9; (362) PS6, PS8, PS9, and PS11; (363) PS5, PS7, PS9, and PS11;(364) PS5, PS6, PS7, and PS9; (365) PS6 and PS9; (366) PS7, PS8, PS9,and PS11; (367) PS6, PS7, PS8, and PS9; (368) PS3, PS5, PS6, and PS8;(369) PS9 and PS1; (370) PS5, PS6, and PS9; (371) PS5, PS9, and PS11;(372) PS7 and PS9; (373) PS6, PS8, and PS9; (374) PS8, PS9, and PS11;(375) PS5, PS7, and PS9; (376) PS5, PS8, PS9, and PS11; (377) PS5, PS6,PS8, and PS9; (378) PS7, PS8, and PS9; (379) PS5 and PS9; (380) PS5,PS7, PS8, and PS9; (381) PS8 and PS9; (382) PS5, PS8, and PS9; (383)PS5, PS6, PS7, and PS11; (384) PS5, PS6, and PS11; (385) PS5, PS6, andPS7; (386) PS5, PS6, PS8, and PS11; (387) PS5 and PS6; (388) PS5, PS6,PS7, and PS8; (389) PS5, PS6, and PS8; (390) PS3, PS6, PS9, and PS11;(391) PS3, PS6, PS7, and PS9; (392) PS3, PS7, PS9, and PS11; (393) PS3,PS6, and PS9; (394) PS3, PS9, and PS1; (395) PS3, PS5, PS6, and PS9;(396) PS3, PS5, PS9, and PS11; (397) PS3, PS6, PS8, and PS9; (398) PS3,PS7, and PS9; (399) PS3, PS8, PS9, and PS11; (400) PS3, PS5, PS7, andPS9; (401) PS3 and PS9; (402) PS3, PS7, PS8, and PS9; (403) PS3, PS5,and PS9; (404) PS3, PS8, and PS9; (405) PS3, PS5, PS8, and PS9; (406)PS6, PS7, PS9, and PS11; (407) PS3, PS5, PS6, and PS11; (408) PS6, PS9,and PS11; (409) PS3, PS5, PS6, and PS7; (410) PS5, PS6, PS9, and PS11;(411) PS3, PS5, and PS6; (412) PS6, PS7, and PS9; (413) PS7, PS9, andPS11; (414) PS9; (415) PS3, PS9, and PS12; (416) PS9 and PS12; (417) PS3and PS9; (418) PS5, PS7, PS12, and PS14; (419) PS5, PS12, and PS13;(420) PS5, PS7, PS12, and PS13; (421) PS5, PS12, PS13, and PS14; (422)PS5, PS8, PS12, and PS13; (423) PS3, PS5, PS12, and PS13; (424) PS5,PS12, and PS14; (425) PS1, PS5, PS12, and PS14; (426) PS5, PS11, PS12,and PS14; (427) PS1, PS5, PS12, and PS13; (428) PS5, PS11, PS12, andPS13; (429) PS5, PS8, PS12, and PS14; (430) PS3, PS5, PS12, and PS14;(431) PS1, PS4, PS9, and PS11; (432) PS8, PS9, and PS13; (433) PS8, PS9,PS11, and PS14; (434) PS3, PS8, PS9, and PS14; (435) PS8, PS9, PS11, andPS13; (436) PS3, PS8, PS9, and PS13; (437) PS8, PS9, PS13, and PS14;(438) PS2, PS8, PS9, and PS14; (439) PS8, PS9, PS12, and PS14; (440)PS8, PS9, and PS14; (441) PS2, PS8, PS9, and PS13; (442) PS8, PS9, PS12,and PS13; (443) PS4 and PS9; (444) PS3, PS4, PS9, and PS12; (445) PS4,PS9, and PS12; (446) PS3, PS4, and PS9; (447) PS1, PS5, PS7, and PS12;(448) PS5, PS7, and PS12; (449) PS3, PS5, PS7, and PS12; (450) PS5, PS7,PS11, and PS12; (451) PS5, PS7, PS8, and PS12; (452) PS2 and PS5; (453)PS2, PS3, PS5, and PS9; (454) PS2, PS5, and PS12; (455) PS2, PS5, andPS9; (456) PS2, PS3, and PS5; (457) PS2, PS5, PS9, and PS12; (458) PS2,PS3, PS5, and PS12; (459) PS2, PS4, and PS5; (460) PS2, PS4, PS5, andPS12; (461) PS2, PS4, PS5, and PS9; (462) PS2, PS3, PS4, and PS5; (463)PS9, PS11, and PS14; (464) PS9, PS11, and PS13; (465) PS3, PS9, PS11,and PS14; (466) PS9, PS1, PS13, and PS14; (467) PS3, PS9, PS11, andPS13; (468) PS9, PS11, PS12, and PS14; (469) PS2, PS9, PS11, and PS14;(470) PS9, PS11, PS12, and PS13; (471) PS2, PS9, PS11, and PS13; (472)PS1, PS9, and PS14; (473) PS1, PS9, and PS13; (474) PS1, PS8, PS9, andPS13; (475) PS1, PS3, PS9, and PS14; (476) PS1, PS5, PS9, and PS14;(477) PS1, PS9, PS13, and PS14; (478) PS1, PS3, PS9, and PS13; (479)PS1, PS6, PS9, and PS14; (480) PS1, PS5, PS9, and PS13; (481) PS1, PS5,PS6, and PS14; (482) PS1, PS6, PS9, and PS13; (483) PS1, PS5, PS6, andPS13; (484) PS1, PS9, PS11, and PS14; (485) PS1, PS7, PS9, and PS14;(486) PS1, PS8, PS9, and PS14; (487) PS1, PS9, PS11, and PS13; (488)PS1, PS7, PS9, and PS13; (489) PS1 and PS9; (490) PS1, PS6, PS7, andPS9; (491) PS1, PS5, PS9, and PS11; (492) PS1, PS8, PS9, and PS11; (493)PS1, PS5, PS8, and PS9; (494) PS1, PS3, PS7, and PS9; (495) PS1, PS3,and PS9; (496) PS1, PS7, and PS9; (497) PS1, PS5, PS6, and PS9; (498)PS1, PS3, PS6, and PS9; (499) PS1, PS6, PS8, and PS9; (500) PS1, PS3,PS5, and PS6; (501) PS1, PS5, PS6, and PS8; (502) PS1, PS3, PS9, andPS11; (503) PS1, PS3, PS5, and PS9; (504) PS1, PS3, PS8, and PS9; (505)PS1, PS6, and PS9; (506) PS1, PS5, and PS6; (507) PS1, PS5, PS6, andPS7; (508) PS1, PS7, PS9, and PS11; (509) PS1, PS9, and PS11; (510) PS1,PS5, PS7, and PS9; (511) PS1, PS5, and PS9; (512) PS1, PS7, PS8, andPS9; (513) PS1, PS8, and PS9; (514) PS1, PS6, PS9, and PS11; (515) PS1,PS5, PS6, and PS11; (516) PS2 and PS14; (517) PS2, PS5, and PS9; (518)PS2, PS3, PS6, and PS7; (519) PS2, PS3, PS7, and PS13; (520) PS1, PS2,and PS14; (521) PS1, PS2, PS7, and PS8; (522) PS2, PS7, PS8, and PS9;(523) PS2, PS9, and PS14; (524) PS2, PS3, PS11, and PS14; (525) PS2,PS3, PS12, and PS14; (526) PS1, PS2, PS6, and PS11; (527) PS1, PS2,PS11, and PS13; (528) PS2, PS9, PS1, and PS13; (529) PS2, PS6, PS9, andPS11; (530) PS1, PS2, PS6, and PS12; (531) PS1, PS2, PS12, and PS13;(532) PS2, PS9, PS12, and PS13; (533) PS2, PS6, PS9, and PS12; (534)PS2, PS3, PS8, and PS9; (535) PS2, PS7, and PS11; (536) PS2, PS5, andPS14; (537) PS2, PS7, and PS12; (538) PS2, PS5, PS11, and PS13; (539)PS2, PS5, PS12, and PS13; (540) PS2, PS6, PS8, and PS13; (541) PS2 andPS9; (542) PS2, PS3, PS6, and PS13; (543) PS1, PS2, PS8, and PS13; (544)PS1, PS2, PS3, and PS7; (545) PS2, PS3, PS7, and PS9; (546) PS1, PS2,PS9, and PS11; (547) PS1, PS2, PS9, and PS12; (548) PS2, PS5, PS7, andPS8; (549) PS2, PS5, PS6, and PS11; (550) PS2, PS7, PS8, and PS14; (551)PS2, PS5, PS6, and PS12; (552) PS2, PS6, PS7, and PS13; (553) PS2, PS3,PS5, and PS7; (554) PS2, PS11, PS13, and PS14; (555) PS2, PS6, PS11, andPS14; (556) PS2, PS12, PS13, and PS14; (557) PS2, PS6, PS12, and PS14;(558) PS1, PS2, PS7, and PS13; (559) PS2, PS3, PS8, and PS14; (560) PS1,PS2, PS6, and PS8; (561) PS2, PS8, PS9, and PS13; (562) PS2, PS6, PS8,and PS9; (563) PS1, PS2, PS3, and PS6; (564) PS1, PS2, PS3, and PS13;(565) PS2, PS3, PS9, and PS13; (566) PS2, PS7, and PS8; (567) PS2, PS6,and PS11; (568) PS2, PS11, and PS13; (569) PS2, PS5, PS6, and PS8; (570)PS2, PS5, PS8, and PS13; (571) PS2, PS12, and PS13; (572) PS2, PS6, andPS12; (573) PS2, PS8, PS13, and PS14; (574) PS2, PS3, PS7, and PS14;(575) PS1, PS2, PS6, and PS7; (576) PS2, PS5, PS9, and PS11; (577) PS2,PS7, PS9, and PS13; (578) PS2, PS5, PS9, and PS12; (579) PS2, PS6, PS7,and PS9; (580) PS1, PS2, PS11, and PS14; (581) PS2, PS9, PS11, and PS14;(582) PS1, PS2, PS12, and PS14; (583) PS2, PS9, PS12, and PS14; (584)PS2, PS3, PS6, and PS9; (585) PS1, PS2, PS8, and PS9; (586) PS2, PS5,PS6, and PS7; (587) PS2, PS5, PS7, and PS13; (588) PS1, PS2, PS3, andPS9; (589) PS2, PS5, PS11, and PS14; (590) PS2, PS8, and PS13; (591)PS2, PS7, PS11, and PS12; (592) PS2, PS3, and PS7; (593) PS2, PS7, PS13,and PS14; (594) PS2, PS5, PS12, and PS14; (595) PS2, PS6, PS8, and PS14;(596) PS2, PS3, PS5, and PS13; (597) PS2, PS3, PS5, and PS6; (598) PS2,PS9, and PS11; (599) PS2, PS5, PS8, and PS9; (600) PS2, PS9, and PS12;(601) PS2, PS3, PS6, and PS14; (602) PS2, PS3, PS13, and PS14; (603)PS1, PS2, PS8, and PS14; (604) PS1, PS2, PS6, and PS13; (605) PS2, PS6,PS9, and PS13; (606) PS1, PS2, PS7, and PS9; (607) PS2, PS7, and PS13;(608) PS2, PS6, and PS8; (609) PS2, PS6, PS7, and PS14; (610) PS1, PS2,PS5, and PS7; (611) PS2, PS5, PS7, and PS9; (612) PS2, PS3, and PS6;(613) PS2, PS3, and PS13; (614) PS1, PS2, PS7, and PS14; (615) PS2, PS8,PS9, and PS14; (616) PS2, PS3, PS5, and PS9; (617) PS1, PS2, PS3, andPS14; (618) PS2, PS3, PS9, and PS14; (619) PS1, PS2, PS9, and PS13;(620) PS1, PS2, PS6, and PS9; (621) PS2, PS6, and PS7; (622) PS2, PS7,PS8, and PS11; (623) PS2, PS11, and PS14; (624) PS2, PS5, PS8, and PS14;(625) PS2, PS7, PS8, and PS12; (626) PS2, PS5, PS6, and PS13; (627) PS2,PS12, and PS14; (628) PS1, PS2, and PS7; (629) PS2, PS11, PS12, andPS13; (630) PS2, PS6, PS11, and PS12; (631) PS2, PS6, PS13, and PS14;(632) PS2, PS8, and PS9; (633) PS2, PS7, PS9, and PS14; (634) PS1, PS2,PS5, and PS13; (635) PS2, PS3, and PS9; (636) PS2, PS5, PS7, and PS14;(637) PS2, PS8, and PS14; (638) PS2, PS6, and PS13; (639) PS2, PS8,PS11, and PS13; (640) PS2, PS7, and PS9; (641) PS2, PS3, PS7, and PS11;(642) PS2, PS8, PS12, and PS13; (643) PS2, PS3, PS5, and PS14; (644)PS2, PS3, PS7, and PS12; (645) PS1, PS2, PS5, and PS6; (646) PS2, PS5,PS6, and PS9; (647) PS2, PS5, PS9, and PS13; (648) PS1, PS2, PS6, andPS14; (649) PS1, PS2, PS13, and PS14; (650) PS2, PS9, PS11, and PS12;(651) PS2, PS9, PS13, and PS14; (652) PS2, PS6, PS9, and PS14; (653)PS2, PS5, and PS7; (654) PS2, PS7, and PS14; (655) PS2, PS7, PS11, andPS13; (656) PS2, PS5, PS13, and PS14; (657) PS2, PS7, PS12, and PS13;(658) PS2, PS6, PS8, and PS11; (659) PS2, PS6, PS8, and PS12; (660) PS2,PS3, PS7, and PS8; (661) PS2, PS3, and PS14; (662) PS1, PS2, and PS6;(663) PS1, PS2, and PS13; (664) PS2, PS6, and PS9; (665) PS2, PS9, andPS13; (666) PS2, PS3, PS6, and PS11; (667) PS2, PS3, PS11, and PS13;(668) PS2, PS3, PS12, and PS13; (669) PS2, PS3, PS6, and PS12; (670)PS1, PS2, PS5, and PS9; (671) PS2 and PS7; (672) PS1, PS2, PS9, andPS14; (673) PS2, PS5, and PS13; (674) PS2, PS6, PS7, and PS11; (675)PS2, PS5, PS6, and PS14; (676) PS2, PS6, PS7, and PS12; (677) PS2, PS11,PS12, and PS14; (678) PS1, PS2, PS7, and PS11; (679) PS1, PS2, PS5, andPS14; (680) PS1, PS2, PS7, and PS12; (681) PS2, PS8, PS9, and PS11;(682) PS2, PS8, PS9, and PS12; (683) PS1, PS2, and PS9; (684) PS2, PS3,PS9, and PS11; (685) PS2, PS3, PS9, and PS12; (686) PS2, PS5, and PS6;(687) PS2, PS7, PS8, and PS13; (688) PS2, PS6, and PS14; (689) PS2,PS13, and PS14; (690) PS2, PS6, PS7, and PS8; (691) PS2, PS8, PS11, andPS14; (692) PS2, PS6, PS11, and PS13; (693) PS2, PS8, PS12, and PS14;(694) PS2, PS6, PS12, and PS13; (695) PS2, PS7, PS9, and PS11; (696)PS2, PS5, PS9, and PS14; (697) PS2, PS7, PS9, and PS12; (698) PS2, PS3,PS6, and PS8; (699) PS2, PS3, PS8, and PS13; (700) PS2 and PS13; (701)PS2, PS5, PS7, and PS11; (702) PS2, PS5, PS7, and PS12; (703) PS2, PS7,PS11, and PS14; (704) PS2, PS7, PS12, and PS14; (705) PS5; (706) PS5,PS8, and PS11; (707) PS3 and PS5; (708) PS3, PS5, and PS11; (709) PS5and PS11; (710) PS3, PS5, and PS8; (711) PS3, PS5, PS8, and PS11; (712)PS5 and PS8; (713) PS5; (714) PS3, PS5, PS9, and PS12; (715) PS5, PS9,and PS12; (716) PS3, PS5, and PS12; (717) PS3, PS5, and PS9; (718) PS5and PS12; (719) PS5 and PS9; (720) PS3 and PS5; (721) PS9 and PS13;(722) PS2, PS9, and PS13; (723) PS3, PS9, PS12, and PS14; (724) PS9,PS12, PS13, and PS14; (725) PS2, PS9, PS12, and PS14; (726) PS3, PS9,PS13, and PS14; (727) PS9, PS12, and PS14; (728) PS2, PS3, PS9, andPS14; (729) PS2, PS9, PS13, and PS14; (730) PS3, PS9, and PS14; (731)PS9, PS13, and PS14; (732) PS2, PS9, and PS14; (733) PS9 and PS14; (734)PS3, PS9, PS12, and PS13; (735) PS2, PS9, PS12, and PS13; (736) PS9,PS12, and PS13; (737) PS2, PS3, PS9, and PS13; (738) PS3, PS9, and PS13;(739) PS1, PS4, PS5, and PS11; (740) PS4, PS8, PS9, and PS13; (741) PS4,PS8, PS9, and PS14; (742) PS2 and PS5; (743) PS2, PS5, PS8, and PS11;(744) PS2, PS3, PS5, and PS11; (745) PS1, PS2, PS5, and PS12; (746) PS2,PS5, and PS12; (747) PS1, PS2, and PS5; (748) PS2, PS3, PS5, and PS8;(749) PS2, PS5, PS11, and PS12; (750) PS1, PS2, PS5, and PS11; (751)PS2, PS5, and PS11; (752) PS2, PS5, PS8, and PS12; (753) PS2, PS3, PS5,and PS12; (754) PS2, PS3, and PS5; (755) PS2, PS5, and PS8; (756) PS1,PS2, PS5, and PS8; (757) PS1, PS2, PS3, and PS5; (758) PS4 and PS5;(759) PS4, PS5, PS9, and PS12; (760) PS3, PS4, PS5, and PS12; (761) PS3,PS4, PS5, and PS9; (762) PS4, PS5, and PS12; (763) PS4, PS5, and PS9;(764) PS3, PS4, and PS5; (765) a set of one or more PSs in a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, and (766) a set ofone or more PSs in a substitute haplotype for any of haplotypes(1)-(764) in Table 1.

In a preferred embodiment of the kit of the invention, the set of one ormore oligonucleotides is designed for identifying both alleles at eachPS in the set of one or more PSs. In another preferred embodiment, theindividual is Caucasian. In another preferred embodiment, the kitfurther comprises a manual with instructions for (a) performing one ormore reactions on a human nucleic acid sample to identify the allele oralleles present in the individual at each PS in the set of one or morePSs, and (b) determining if the individual has an age of onset marker Ior an age of onset marker II based on the identified allele or alleles.In another preferred embodiment, the linkage disequilibrium between thelinked haplotype and at least one of haplotypes (1)-(764) in Table 1 hasa delta squared value selected from the group consisting of at least0.75, at least 0.80, at least 0.85, at least 0.90, at least 0.95, and1.0. In yet another preferred embodiment, the linkage disequilibriumbetween the allele at a substituting PS in the substitute haplotype andthe allele at a substituted PS in any of haplotypes (1)-(764) in Table 1has a delta squared value selected from the group consisting of at least0.75, at least 0.80, at least 0.85, at least 0.90, at least 0.95, and1.0.

As used herein, an “oligonucleotide” is a probe or primer capable ofhybridizing to a target region that contains, or that is located closeto, a PS of interest. Preferably, the oligonucleotide has less thanabout 100 nucleotides. More preferably, the oligonucleotide is 10 to 35nucleotides long. Even more preferably, the oligonucleotide is between15 and 30, and most preferably, between 20 and 25 nucleotides in length.The exact length of the oligonucleotide will depend on the nature of thegenomic region containing the PS as well as the genotyping assay to beperformed and is readily determined by the skilled artisan.

The oligonucleotides used to practice the invention may be comprised: ofany phosphorylation state of ribonucleotides, deoxyribonucleotides, andacyclic nucleotide derivatives, and other functionally equivalentderivatives. Alternatively, oligonucleotides may have a phosphate-freebackbone, which may be comprised of linkages such as carboxymethyl,acetamidate, carbamate, polyamide (peptide nucleic acid (PNA)) and thelike (Varma, in Molecular Biology And Biotechnology, A ComprehensiveDesk Reference, Meyers, ed., VCH Publishers, Inc. (1995), pp. 617-20).Oligonucleotides of the invention may be prepared by chemical synthesisusing any suitable methodology known in the art, or may be derived froma biological sample, for example, by restriction digestion. Theoligonucleotides may be labeled, according to any technique known in theart, including use of radiolabels, fluorescent labels, enzymatic labels,proteins, haptens, antibodies, sequence tags and the like.

Oligonucleotides of the invention must be capable of specificallyhybridizing to a target region of a polynucleotide containing a desiredlocus. As used herein, specific hybridization means the oligonucleotideforms an anti-parallel double-stranded structure with the target regionunder certain hybridizing conditions, while failing to form such astructure when incubated with another region in the polynucleotide orwith a polynucleotide lacking the desired locus under the samehybridizing conditions. Preferably, the oligonucleotide specificallyhybridizes to the target region under conventional high stringencyconditions.

A nucleic acid molecule such as an oligonucleotide or polynucleotide issaid to be a “perfect” or “complete” complement of another nucleic acidmolecule if every nucleotide of one of the molecules is complementary tothe nucleotide at the corresponding position of the other molecule. Anucleic acid molecule is “substantially complementary” to anothermolecule if it hybridizes to that molecule with sufficient stability toremain in a duplex form under conventional low-stringency conditions.Conventional hybridization conditions are described, for example, inSambrook et al., Molecular Cloning, A Laboratory Manual, 2nd ed., ColdSpring Harbor Press, Cold Spring Harbor, N.Y. (1989), and in Haymes etal., Nucleic Acid Hybridization, A Practical Approach, IRL Press,Washington, D.C. (1985). While perfectly complementary oligonucleotidesare preferred for detecting polymorphisms, departures from completecomplementarity are contemplated where such departures do not preventthe molecule from specifically hybridizing to the target region. Forexample, an oligonucleotide primer may have a non-complementary fragmentat its 5′ end, with the remainder of the primer being complementary tothe target region. Alternatively, non-complementary nucleotides may beinterspersed into the probe or primer as long as the resulting probe orprimer is still capable of specifically hybridizing to the targetregion.

Preferred oligonucleotides of the invention, useful in determining if anindividual has an age of onset marker I or an age of onset marker II,are allele-specific oligonucleotides. As used herein, the termallele-specific oligonucleotide (ASO) means an oligonucleotide that isable, under sufficiently stringent conditions, to hybridize specificallyto one allele of a gene, or other locus, at a target region containing aPS while not hybridizing to the corresponding region in anotherallele(s). As understood by the skilled artisan, allele-specificity willdepend upon a variety of readily optimized stringency conditions,including salt and formamide concentrations, as well as temperatures forboth the hybridization and washing steps. Examples of hybridization andwashing conditions typically used for ASO probes are found in Kogan etal., “Genetic Prediction of Hemophilia A” in PCR Protocols, A Guide ToMethods And Applications, Academic Press (1990), and Ruaño et al., Proc.Natl. Acad. Sci. USA 87:6296-6300 (1990). Typically, an ASO will beperfectly complementary to one allele while containing a single mismatchfor another allele.

Allele-specific oligonucleotides of the invention include ASO probes andASO primers. ASO probes which usually provide good discriminationbetween different alleles are those in which a central position of theoligonucleotide probe aligns with the polymorphic site in the targetregion (e.g., approximately the 7th or 8th position in a 15mer, the 8thor 9th position in a 16mer, and the 10th or 11th position in a 20mer).An ASO primer of the invention has a 3′ terminal nucleotide, orpreferably a 3′ penultimate nucleotide, that is complementary to onlyone of the nucleotide alleles of a particular SNP, thereby acting as aprimer for polymerase-mediated extension only if that nucleotide alleleis present at the PS in the sample being genotyped. ASO probes andprimers hybridizing to either the coding or noncoding strand arecontemplated by the invention. ASO probes and primers listed below usethe appropriate nucleotide symbol (R=G or A, Y=T or C, M=A or C, K=G orT, S=G or C, and W=A or T/U; WIPO standard ST.25) at the position of thePS to represent that the ASO contains either of the two alternativeallelic variants observed at that PS.

A preferred ASO probe for detecting the alleles at each of PS1, PS2,PS3, PS4, PS5, PS6, PS7, PS8, PS9, PS11, PS12, PS13, and PS14 is listedin Table 4. Additionally, detection of the alleles at each of PS1, PS2,PS3, PS4, PS5, PS6, PS7, PS8, PS9, PS11, PS12, PS13, and PS14 could beaccomplished by utilization of the complement of these ASO probes.

A preferred ASO forward and reverse primer for detecting the alleles ateach of PS1, PS2, PS3, PS4, PS5, PS6, PS7, PS8, PS9, PS11, PS12, PS13,and PS14 is listed in Table 4. TABLE 4 Preferred ASOs for DetectingAlleles at PSs in Haplotypes Comprising Preferred Embodiments of Age ofOnset Markers I and II¹ ASO ASO ASO Probe Forward Primer Reverse PrimerSEQ SEQ SEQ ID ID ID PS Sequence NO. Sequence NO. Sequence NO. 1AATGGCAYGG 2 TGGGGTAATGGC 15 TGGGAAGGACC 28 GGTCC AYG CCRT 2 ACAGATGYGA3 TGGGCGACAGAT 16 ACTCGTTTCTT 29 AAGAA GYG TCRC 3 AGCTCACSGC 4AATCACAGCTCA 17 AGGCAGAGGCT 30 AGCCT CSG GCSG 4 CACGAAGRCC 5CCCCCACACGAA 18 ACAGCCTTGCA 31 TGCAA GRC GGYC 5 AGGAAGGRGC 6GGGAGCAGGAAG 19 CAGTTCCTGAA 32 TTCAG GRG GCYC 6 GCACTGGYGC 7TGGAGTGCACTG 20 GAGCTACGATT 33 AATCG GYG GCRC 7 CCTCAGGMCC 8CCAGGCCCTCAG 21 CAGTCCCAGAG 34 CTCTG GMC GGKC 8 GCCGCCTYTA 9TCAGTGGCCGCC 22 AGTCAACCCAG 35 CTGGG TYT TARA 9 ATGTCAAYGG 10GCATCGATGTCA 23 TCCGGTTGCCC 36 GGGCA AYG CCRT 11 CAGGTGTRGC 11GCCTCACAGGTG 24 ACAAGGCGTGT 37 ACACG TRG GCYA 12 TTCTTGGRTG 12ATACTTTTCTTG 25 GCTGATGTGTC 38 GACAC GRT CAYC 13 ACTCACCRTC 13TCCGGTACTCAC 26 CGCCAGAGGGA 39 TCCCT CRT GAYG 14 GGCCCAGRAG 14CTGCCAGGCCCA 27 CTACTTCTCAC 40 GTGAG GRA CTYC¹These ASO probes and primers include the appropriate nucleotide symbol,Y = T or C, R = G or A, M = A or C, S = G or C, and W = A or T/U (WorldIntellectual Property Organization Handbook on Industrial PropertyInformation and Documentation IPO Standard ST.25 (1998), Appendix 2,Table 1), at the position of the PS to represent that the ASO containsone of the two alternative polymorphisms observed at that position.

Other oligonucleotides useful in practicing the invention hybridize to atarget region located one to several nucleotides downstream of a PS inan age of onset marker. Such oligonucleotides are useful inpolymerase-mediated primer-extension methods for detecting an allele atone of the PSs in the markers described herein and therefore sucholigonucleotides are referred to herein as “primer-extensionoligonucleotides.” In a preferred embodiment, the 3′-terminus of aprimer-extension oligonucleotide is a deoxynucleotide complementary tothe nucleotide located immediately adjacent to the PS. A particularlypreferred forward and reverse primer-extension oligonucleotide fordetecting the alleles at each of PS1, PS2, PS3, PS5, PS6, PS7, PS9, andPS10 is listed in Table 5. Termination mixes are chosen to terminateextension of the oligonucleotide at the PS of interest, or one basethereafter, depending on the alternative nucleotides present at the PS.TABLE 5 Preferred Primer Extension Oligonucleotides for DetectingAlleles at PSs in Haplotypes Comprising Preferred Embodiments of Age ofOnset Markers I and II Forward Reverse Primer Extension Primer ExtensionPS Sequence SEQ ID NO. Sequence SEQ ID NO. 1 GGTAATGGCA 41 GAAGGACCCC 542 GCGACAGATG 42 CGTTTCTTTC 55 3 CACAGCTCAC 43 CAGAGGCTGC 56 4 CCACACGAAG44 GCCTTGCAGG 57 5 AGCAGGAAGG 45 TTCCTGAAGC 58 6 AGTGCACTGG 46CTACGATTGC 59 7 GGCCCTCAGG 47 TCCCAGAGGG 60 8 GTGGCCGCCT 48 CAACCCAGTA61 9 TCGATGTCAA 49 GGTTGCCCCC 62 11 TCACAGGTGT 50 AGGCGTGTGC 63 12CTTTTCTTGG 51 GATGTGTCCA 64 13 GGTACTCACC 52 CAGAGGGAGA 65 14 CCAGGCCCAG53 CTTCTCACCT 66In some embodiments, the oligonucleotides in a kit of the invention havedifferent labels to allow probing of the identity of nucleotides ornucleotide pairs at two or more PSs simultaneously.

The oligonucleotides in a kit of the invention may also be immobilizedon or synthesized on a solid surface such as a microchip, bead, or glassslide (see, e.g., WO 98/20020 and WO 98/20019). Such immobilizedoligonucleotides may be used in a variety of polymorphism detectionassays, including but not limited to probe hybridization and polymeraseextension assays. Immobilized oligonucleotides useful in practicing theinvention may comprise an ordered array of oligonucleotides designed torapidly screen a nucleic acid sample for polymorphisms in multiple genesat the same time.

Kits of the invention may also contain other components such ashybridization buffer (e.g., where the oligonucleotides are to be used asallele-specific probes) or dideoxynucleotide triphosphates (ddNTPs;e.g., where the alleles at the polymorphic sites are to be detected byprimer extension). In a preferred embodiment, the set ofoligonucleotides consists of primer-extension oligonucleotides. The kitmay also contain a polymerase and a reaction buffer optimized forprimer-extension mediated by the polymerase. Preferred kits may alsoinclude detection reagents, such as biotin- or fluorescent-taggedoligonucleotides or ddNTPs and/or an enzyme-labeled antibody and one ormore substrates that generate a detectable signal when acted on by theenzyme. It will be understood by the skilled artisan that the set ofoligonucleotides and reagents for performing the genotyping orhaplotyping assay will be provided in separate receptacles placed in thecontainer if appropriate to preserve biological or chemical activity andenable proper use in the assay.

In a particularly preferred embodiment, each of the oligonucleotides andall other reagents in the kit have been quality tested for optimalperformance in an assay for determining the alleles at a set of PSscomprising an age of onset marker I or age of onset marker II.

The invention provides a method for predicting the age of onset of AD inan individual at risk for developing AD. The method comprisesdetermining whether the individual has an age of onset marker I or anage of onset marker II, and making an age of onset prediction based onthe results of the determining step. The determination of the age ofonset marker present in an individual can be made using one of thedirect or indirect methods described herein. In some preferredembodiments, the determining step comprises identifying for one or bothcopies of the genomic locus present in the individual the identity ofthe nucleotide or nucleotide pair at the set of PSs comprising theselected age of onset marker. Alternatively, the determining step maycomprise consulting a data repository that states the individual's copynumber for the haplotypes comprising one of the age of onset markers Ior age of onset markers II. The data repository may be the individual'smedical records or a medical data card. In preferred embodiments, theindividual is Caucasian.

According to Table 8 below, if the individual is determined to have anage of onset marker I, then the prediction is that the individual's ageof onset of AD will be between 72.1 and 73.9, and if the individual isdetermined to have an age of onset marker II, then the prediction isthat the individual's age of onset of AD will be between 68.3 and 72.2.

The invention further provides a method for delaying the onset of AD inan individual at risk for developing AD. The method comprisesdetermining whether the individual has an age of onset marker I or anage of onset marker II, and making a treatment decision based upon theresults of the determining step. In some embodiments, the determiningstep comprises identifying for one or both copies of the genomic locuspresent in the individual the identity of the nucleotide or nucleotidepair at the set of PSs comprising the selected haplotype. Alternatively,the determining step may comprise consulting a data repository thatstates the individual's copy number for a haplotype comprising an age ofonset marker I or an age of onset marker II. The data repository may bethe individual's medical records or a medical data card. In preferredembodiments, the individual is Caucasian.

If the individual is determined to have an age of onset marker I, thetreatment decision is to prescribe to the individual a compoundeffective in delaying the onset of AD, wherein the compound isprescribed to the individual at an age below that of the lowerconfidence interval of the least square mean of age of onset for the ageof onset marker I. If the individual is determined to have an age ofonset marker II, the treatment decision is to prescribe to theindividual at an age below that of the lower confidence interval of theleast square mean of age of onset for the age of onset marker II.According to Table 8 below, the lower confidence interval of the leastsquare mean of age of onset for an age of onset marker I ranges from72.4 to 75.3, and the lower confidence interval of the least square meanof age of onset for an age of onset marker II ranges from 64.1 to 71.3.

In other aspects, the invention provides an article of manufacture. Inone embodiment, an article of manufacture comprises a pharmaceuticalformulation and at least one indicium identifying a population for whichthe pharmaceutical formulation is indicated. The pharmaceuticalformulation comprises, as at least one active ingredient, a compoundeffective in delaying the onset of AD in an individual at risk fordeveloping AD. Additionally, the pharmaceutical formulation may beregulated and the indicium may comprise the approved label for thepharmaceutical formulation. The identified population is one that is atrisk for developing AD, and is further partially or wholly defined byhaving an age of onset marker I or an age of onset marker II, wherein atrial population of individuals having an age of onset marker I exhibita later age of onset of AD than a trial population of individuals havingan age of onset marker II. The identified population preferably may befurther defined as Caucasian. In addition to being at risk fordeveloping AD, a population wholly defined by having an age of onsetmarker I or II is one for which there are no other factors which shouldbe considered in identifying the population for which the pharmaceuticalformulation is indicated. In contrast, a population that is partiallydefined by having an age of onset marker I or II is one for which otherfactors may be pertinent to identification of the population for whichthe pharmaceutical formulation is indicated. Examples of other suchfactors are age, weight, gender, disease state, possession of othergenetic markers or biomarkers, or the like.

The pharmaceutical formulation may be formulated, in any way known inthe art, for any mode of delivery (i.e., oral), and any mode of release(i.e., sustained release). In some embodiments, the pharmaceuticalformulation is a tablet or capsule and the article may further comprisean additional indicium comprising the color or shape of the table orcapsule. In other embodiments, the article may further comprise anadditional indicium comprising a symbol stamped on the tablet orcapsule, or a symbol or logo printed on the approved label.

In some embodiments of this article, the approved label may comprise astatement that the pharmaceutical formulation is indicated for delayingthe onset of AD in an individual at risk for developing AD. In someembodiments, the approved label may further state the lower confidenceinterval of the least square mean of age of onset of AD for individualshaving an age of onset marker I, and the lower confidence interval ofthe least square mean of age of onset of AD for individuals having anage of onset marker II.

An additional embodiment of the article of manufacture provided by theinvention comprises packaging material and a pharmaceutical formulationcontained within said packaging material. The pharmaceutical formulationcomprises, as at least one active ingredient, a compound effective indelaying the onset of AD in an individual at risk for developing AD.Additionally, the packaging material may comprise a label stating thatthe pharmaceutical formulation is indicated for a population at risk fordeveloping AD and which is partially or wholly defined by having an ageof onset marker I or an age of onset marker II, and preferably furtherstating that a trial population of individuals having an age of onsetmarker I exhibit a later age of onset of AD than a trial population ofindividuals having an age of onset marker II. The indicated populationpreferably may be further defined as Caucasian.

Additionally, in other aspects of the invention, a method ofmanufacturing a drug product comprising, as at least one activeingredient, a compound effective in delaying the onset of AD in anindividual at risk for developing AD is provided. The method comprisescombining in a package a pharmaceutical formulation comprising thecompound and a label that states that the formulation is indicated fordelaying the onset of AD in a population at risk for developing AD andwhich is partially or wholly defined by having an age of onset marker Ior an age of onset marker II, wherein a trial population having an ageof onset marker I exhibits a later age of onset of AD than a trialpopulation having an age of onset marker II. The indicated populationmay be identified on the pharmaceutical formulation, on the label or onthe package by at least one indicium, such as a symbol or logo, color,or the like. The indicated population preferably may be further definedas Caucasian.

Detecting the presence of an age of onset marker I or an age of onsetmarker II in an individual is also useful in a method for seekingregulatory approval for marketing a pharmaceutical formulation fordelaying the onset of AD in a population at risk for developing AD,wherein the population is partially or wholly defined by having an ageof onset marker I or an age of onset marker II. The method comprisesconducting at least one clinical trial which comprises administering thepharmaceutical formulation to first and second groups of individuals atrisk for developing AD, and administering a placebo to third and fourthgroups of individuals at risk for developing AD, wherein each individualin the first and third groups has an age of onset marker I, and eachindividual in the second and fourth groups has an age of onset markerII, demonstrating that the first group exhibits a later age of onset ofAD than the third group, and demonstrating that the second groupexhibits a later age of onset than the fourth group, and filing with aregulatory agency an application for marketing approval of thepharmaceutical formulation with a label stating that the pharmaceuticalformulation is indicated for delaying the onset of AD in individuals atrisk for developing AD. In preferred embodiments, the regulatory agencyis the United States Food and Drug Administration (FDA) or the EuropeanAgency for the Evaluation of Medicinal Products (EMEA), or a futureequivalent of these agencies.

The clinical trial may be conducted by recruiting individuals at riskfor developing AD, determining whether they have an age of onset markerI or an age of onset marker II, and assigning them to the first andthird groups if they have an age of onset marker I, and assigning themto the second and fourth groups if they have an age of onset marker II.The individuals in each of the first and second groups are preferablyadministered the same dose of the pharmaceutical formulation, and theindividuals in each of the third and fourth groups are preferablyadministered the same does of the placebo.

The regulatory agency may be any person or group authorized by thegovernment of a country anywhere in the world to control the marketingor distribution of drugs in that country. Preferably, the regulatoryagency is authorized by the government of a major industrializedcountry, such as Australia, Canada, China, a member of the EuropeanUnion, Japan, and the like. Most preferably the regulatory agency isauthorized by the government of the United States and the type ofapplication for approval that is filed will depend on the legalrequirements set forth in the last enacted version of the Food, Drug andCosmetic Act that are applicable for the pharmaceutical formulation andmay also include other considerations such as the cost of making theregulatory filing and the marketing strategy for the composition. Forexample, if the pharmaceutical formulation has previously been approvedfor the same cognitive function, then the application might be a paperNDA, a supplemental NDA or an abbreviated NDA, but the application wouldbe a full NDA if the pharmaceutical formulation has never been approvedbefore; with these terms having the meanings applied to them by thoseskilled in the pharmaceutical arts or as defined in the Drug PriceCompetition and Patent Term Restoration Act of 1984.

Additionally, in other aspects of the invention, there is provided amethod for marketing a drug product comprising promoting to a targetaudience the use of a drug product for delaying the onset of AD in apopulation at risk for developing AD, wherein the population ispartially or wholly defined by having an age of onset marker I or an ageof onset marker II, wherein the drug product comprises a compoundeffective in delaying the onset of AD, and wherein a trial population ofindividuals having an age of onset marker I exhibit a later age of onsetof AD than a trial population having an age of onset marker II. Thetarget audience can be members of a group that is in position toinfluence prescription or purchase of the drug product. Such groupsinclude physicians, pharmacists, insurance companies and healthmaintenance organizations, individuals at risk for developing AD, andgovernment agencies such as those involved in providing or regulatingmedical insurance and those involved in regulating the marketing ofdrugs.

The promoting step can employ printed publications such as medicaljournals and consumer magazines, radio and television advertisements,and public presentations such as presentations at medical and scientificconferences. In a preferred embodiment, the drug product is approved formarketing to delay the onset of AD in the population, and the promotingstep includes a statement that relates the approved drug product to itsappearance, e.g., the color or shape of a tablet or capsule formulation,or some design stamped or embossed thereon.

Further, in performing any of the methods described herein which requireinformation on the haplotype content of the individual (i.e., thehaplotypes and haplotype copy number present in the individual for thepolymorphic sites in haplotypes comprising an age of onset marker I oran age of onset marker IT) or which require knowing if an age of onsetmarker I or an age of onset marker II is present in the individual, theindividual's LDLR haplotype content or age of onset marker may bedetermined by consulting a data repository such as the individual'spatient records, a medical data card, a file (e.g., a flat ASCII file)accessible by a computer or other electronic or non-electronic media onwhich information about the individual's LDLR haplotype content or ageof onset marker can be stored. As used herein, a medical data card is aportable storage device such as a magnetic data card, a smart card,which has an on-board processing unit and which is sold by vendors suchas Siemens of Munich Germany, or a flash-memory card. The medical datacard may be, but does not have to be, credit-card sized so that iteasily fits into pocketbooks, wallets and other such objects carried bythe individual. The medical data card may be swiped through a devicedesigned to access information stored on the data card. In analternative embodiment, portable data storage devices other than datacards can be used. For example, a touch-memory device, such as the“i-button” produced by Dallas Semiconductor of Dallas, Tex. can storeinformation about an individual's LDLR haplotype content or age of onsetmarker, and this device can be incorporated into objects such asjewelry. The data storage device may be implemented so that it canwirelessly communicate with routing/intelligence devices through IEEE802.112 wireless networking technology or through other methods wellknown to the skilled artisan. Further, as stated above, informationabout an individual's haplotype content or age of onset marker can alsobe stored in a file accessible by a computer; such files may be locatedon various media, including: a server, a client, a hard disk, a CD, aDVD, a personal digital assistant such as a Palm Pilot, a tape, a zipdisk, the computer's internal ROM (read-only-memory) or the internet orworldwide web. Other media for the storage of files accessible by acomputer will be obvious to one skilled in the art.

Any or all analytical and mathematical operations involved in practicingthe methods of the present invention may be implemented by a computer.For example, the computer may execute a program that assigns LDLRhaplotype pairs and/or an age of onset marker I or an age of onsetmarker II to individuals based on genotype data inputted by a laboratorytechnician or treating physician. In addition, the computer may outputthe predicted change in cognitive function in age of onset to agalantamine following input of the individual's LDLR haplotype contentor age of onset marker, which was either determined by the computerprogram or input by the technician or physician. Data on which age ofonset markers were detected in an individual may be stored as part of arelational database (e.g., an instance of an Oracle database or a set ofASCII flat files) containing other clinical and/or haplotype data forthe individual. These data may be stored on the computer's hard drive ormay, for example, be stored on a CD ROM or on one or more other storagedevices accessible by the computer. For example, the data may be storedon one or more databases in communication with the computer via anetwork.

It is also contemplated that the above described methods andcompositions of the invention may be utilized in combination withidentifying genotype(s) and/or haplotype(s) for other genomic regions.

Preferred embodiments of the invention are described in the followingexamples. Other embodiments within the scope of the claims herein willbe apparent to one skilled in the art from consideration of thespecification or practice of the invention as disclosed herein. It isintended that the specification, together with the examples, beconsidered exemplary only, with the scope and spirit of the inventionbeing indicated by the claims that follow the examples.

EXAMPLES

The Examples herein are meant to exemplify the various aspects ofcarrying out the invention and are not intended to limit the scope ofthe invention in any way. The Examples do not include detaileddescriptions for conventional methods employed, such as in the synthesisof oligonucleotides or polymerase chain reaction. Such methods are wellknown to those skilled in the art and are described in numerouspublications, for example, Molecular Cloning: A Laboratory Manual, 2nded., supra.

Example 1

This example illustrates the clinical and biochemical characterizationof selected individuals in a cohort of 449 Caucasian patients diagnosedwith AD, each of whom had previously participated in a clinical trial ofgalantamine.

Genomic DNA samples were isolated from blood samples obtained from eachmember of the cohort and genotyped at each of PS1-PS14 (Table 2) usingthe MassARRAY technology licensed from Sequenom (San Diego, Calif.). Inbrief, this genotyping technology involves performing a homogeneousMassEXTEND assay (hME), in which an initial polymerase chain reaction isfollowed by an allele-specific oligonucleotide extension reaction in thesame tube or plate well, and then detecting the extended oligonucleotideby MALDI-TOF mass spectrometry.

For each of the fourteen LDLR polymorphic sites of interest, a genomicDNA sample was amplified in a 8.0 μL multiplexed PCR reaction consistingof 2.5 ng genomic DNA (0.3 ng/μL), 0.85 mL 10× reaction buffer, 0.32units Taq Polymerase, up to five sets of 0.4 pmol each of forward PCRprimer (5′ to 3′) and reverse PCR primer (3′ to 5′) and 1.6 nmol each ofdATP, dCTP, dGTP and dTTP. A total of fourteen reactions were performedcomprising the following polymorphic site groups: (1) PS1; (2) PS2; (3)PS3; (4) PS4; (5) PS5; (6) PS6; (7) PS7; (8) PS8; (9) PS9; (10) PS10;(11) PS11; (12) PS12; (13) PS13; (14) PS14. Forward and Reverse PCRprimers used for each of the fourteen LDLR polymorphic sites consistedof a 10 base universal tag (5′-AGCGGATAAC-3′; SEQ ID NO:67) followed byone of the LDLR-specific sequences shown in Tables 6A and 6B below:TABLE 6A Forward PCR LDLR-specific Primer Sequences used in hME AssaysPS1 AGCGGATAACATAATCACTCCATCCCTGGG (SEQ ID NO:68) PS2AGCGGATAACTGGCAGGAAATAGACACAGG (SEQ ID NO:69) PS3AGCGGATAACTGTTTTGAGACGGAGTCTCG (SEQ ID NO:70) PS4AGCGGATAACAGTGTGAGGAAGGCTTCCAG (SEQ ID NO:71) PS5AGCGGATAACAAGTGCTGGGATTACAGGTG (SEQ ID NO:72) PS6AGCGGATAACCCTGAAGGTTTCCCTCTTTC (SEQ ID NO:73) PS7AGCGGATAACAGTGGATAAGGAGAGGTCAC (SEQ ID NO:74) PS8AGCGGATAACGCCTCTTTTCATCCTCCAAG (SEQ ID NO:75) PS9AGCGGATAACCTGGGTTGACTCCAAACTTC (SEQ ID NO:76) PS10AGCGGATAACTGTGAGGCAGCTCCTCATGTC (SEQ ID NO:77) PS11AGCGGATAACATGAGCAGAGAGAGGCTCAG (SEQ ID NO:78) PS12AGCGGATAACACTCATGAGTCGGGATAACC (SEQ ID NO:79) PS13AGCGGATAACGTGGGAAGTGACTGAATCCG (SEQ ID NO:80) PS14AGCGGATAACCTGTCTCTGCCAACAAATGG (SEQ ID NO:81)

TABLE 6B Reverse PCR LDLR-specific Primer Sequences used in hME AssaysPS1 AGCGGATAACTGCCCCGTTTCCCTTAAATC (SEQ ID NO:82) PS2AGCGGATAACAGACCCACTTGTAGGAGATG (SEQ ID NO:83) PS3AGCGGATAACGAATCACTGGACATCAGAGG (SEQ ID NO:84) PS4AGCGGATAACTTCCCGTGCTCACCCACAG (SEQ ID NO:85) PS5AGCGGATAACTTCATGGGTGCGTATCCACG (SEQ ID NO:86) PS6AGCGGATAACTGGCACGTGTCTGTAATCTC (SEQ ID NO:87) PS7AGCGGATAACAGGTGCTTTTCTGCTAGGTC (SEQ ID NO:88) PS8AGCGGATAACGCACGTGACCTCTCCTTATC (SEQ ID NO:89) PS9AGCGGATAACCATCCTCCAAGATGGTCTTC (SEQ ID NO:90) PS10AGCGGATAACCACTCGCCCAAGTTTACCTG (SEQ ID NO:91) PS11AGCGGATAACGACATGAGGAGCTGCCTCAC (SEQ ID NO:92) PS12AGCGGATAACAGGAAACCAGGCATCAAAGG (SEQ ID NO:93) PS13AGCGGATAACCCTGATCCCCAAGCATGTTC (SEQ ID NO:94) PS14AGCGGATAACAACATGCTTGGGGATCAGGC (SEQ ID NO:95)

PCR thermocycling conditions were: initial denaturation of 95° C. for 15minutes followed by 45 cycles of 94° C. for 20 seconds, 56° C. for 30seconds and 72° C. for 1 minute followed by a final extension of 72° C.for 3 minutes. Following the final extension, unincorporateddeoxynucleotides were degraded by adding 0.48 units of Shrimp AlkalinePhosphatase (SAP) to the PCR reactions and incubation for 20 minutes at37° C. followed by 5 minutes at 85° C. to inactivate the SAP.

Template-dependent primer extension reactions were then performed on themultiplexed PCR products by adding a 2.0 μL volume of an hME cocktailconsisting of 720 pmol each of three dideoxynucleotides and 720 pmol ofone deoxynucleotide, 8.6 pmol of an extension primer, 0.2 μL of 5×Thermosequenase Reaction Buffer, and NanoPure grade water. Thethermocycling conditions for the mass extension reaction were: initialdenaturation for 2 minutes at 94° C. followed by 40 cycles of 94° C. for5 seconds, 40° C. for 5 seconds and 72° C. for 5 seconds. Extensionprimers used to genotype each of the fourteen LDLR polymorphic sites areshown in Table 7 below: TABLE 7 Extension Primers for Genotyping LDLRPolymorphic Sites PS1 ACTTGTGGGGTAATGGCA (SEQ ID NO:47) PS2CTCTCAGTGGGCGACAGATG (SEQ ID NO:48) PS3 TGCTGTGGCACAATCACAGCTCAC (SEQ IDNO:49) PS4 TGGACCCCCACACGAAG (SEQ ID NO:50) PS5 CACTAACCAGTTCCTGAAGC(SEQ ID NO:51) PS6 AGGCTGGAGTGCACTGG (SEQ ID NO:52) PS7TGCTGATGCCAGTCCCAGAGGG (SEQ ID NO:53) PS8 AAGTTTGGAGTCAACCCAGTA (SEQ IDNO:47) PS9 CCATCTCAAGCATCGATGTCAA (SEQ ID NO:48) PS10 CATGTCCCTGGCCAGCAG(SEQ ID NO:49) PS11 GCAGAAACAAGGCGTGTGC (SEQ ID NO:50) PS12TCGGGATAACCATACTTTTCTTGG (SEQ ID NO:51) PS13 TGACTGAATCCGGTACTCACC (SEQID NO:52) PS14 AGGCCACCTACTTCTCACCT (SEQ ID NO:53)

The extension products were desalted prior to analysis by massspectrometry by mixing them with AG50X8 NH₄OAc cation exchange resin.

The desalted multiplexed extension products were applied onto aSpectroCHIP™ using the SpectroPOINT™ 24 pin applicator tool as permanufacturer's instructions (Sequenom Industrial Genomics, Inc. SanDiego, Calif.). The SpectroChip™ was loaded into a Bruker Biflex III™linear time-of flight mass spectrometer equipped with a SCOUT 384 ionsource and data was acquired using XACQ 4.0, MOCTL 2.1, AutoXecute 4.2and XMASS/XTOF 5.0.1 software on an Ultra 5™ work station (SunMicrosystems, Palo Alto Calif.). Mass spectrometry data was subsequentlyanalyzed on a PC running Windows NT 4.0 (Microsoft, Seattle Wash.) withSpectroTYPER™ genotype calling software (Sequenom Industrial Genomics,Inc. San Diego, Calif.).

Example 2

This example illustrates the deduction of haplotypes from the LDLRgenotyping data generated in Example 1.

Haplotypes were estimated from the unphased genotypes using acomputer-implemented algorithm for assigning haplotypes to unrelatedindividuals in a population sample, essentially as described in WO01/80156 (Genaissance Pharmaceuticals, Inc., New Haven, Conn.). In thismethod, haplotypes are assigned directly from individuals who arehomozygous at all sites or heterozygous at no more than one of thevariable sites. This list of haplotypes is then used to deconvolute theunphased genotypes in the remaining (multiply heterozygous) individuals.

A quality control analysis was performed on the deduced haplotypes,which included analysis of the frequencies of the haplotypes andindividual SNPs therein for compliance with principles of Hardy-Weinbergequilibrium.

Example 3

This example illustrates analysis of the LDLR haplotypes in Table 1 forassociation with individuals' age of onset of Alzheimer's Disease.

The statistical analyses compared age of onset of AD in individuals withone copy or two copies vs. zero copies, or zero copies or one copy vs.two copies (within an individual's genome) of a particular allele, usinga logistic regression analysis on two-degrees of freedom to associateage of onset of AD with a particular haplotype. The following covariateswere also included: gender, family history, and smoking.

For the results obtained on the analyses, adjustments were made formultiple comparisons, using a permutation test (Pesarin, MultivariatePermutation Tests: with Applications in Biostatistics, John Wiley andSons, New York (2001)). In this test, a haplotype's data for eachobservation were kept constant, while all the remaining variables(outcome and covariates) were randomly permuted so that covariatesalways stayed with the same outcome. The permutation model was fittedfor each of the several haplotypes, and the lowest p-value was kept. Intotal, 1000 permutations were done. Seven hundred and sixty-four LDLRhaplotypes of at least one polymorphism were identified that show acorrelation with an individual's age of onset of AD. These LDLRhaplotypes are shown above in Table 1, and the unadjusted (“Raw”) andadjusted (“Perm.”) p-values for these 764 haplotypes are shown below inTable 8. TABLE 8 LDLR Haplotypes Having Association with Age of Onset ofAlzheimer's Disease Lower Upper Confidence Confidence Subject Intervalof Interval of Count for Least Square Least Square Least SquareHaplotype Mean of Age Mean of Age of Mean of Age of (# of of Onset (# ofOnset (# of Onset (# of Haplotype Perm. p Raw p copies) copies) copies)copies) (1) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2)78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (2) 0.012 0.000074 328 (0) 72(0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or2) (3) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2(1 or 2) 75.3 (1 or 2) 81 (1 or 2) (4) 0.012 0.000074 328 (0) 72 (0)71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2)(5) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1or 2) 75.3 (1 or 2) 81 (1 or 2) (6) 0.012 0.000074 328 (0) 72 (0) 71.2(0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (7)0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or2) 75.3 (1 or 2) 81 (1 or 2) (8) 0.012 0.000074 328 (0) 72 (0) 71.2 (0)72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (9) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (10) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (11) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (12) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (13) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (14) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (15) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (16) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (17) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (18) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (19) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (20) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (21) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (22) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (23) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (24) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (25) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (26) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (27) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (28) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (29) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (30) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (31) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (32) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (33) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (34) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (35) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (36) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (37) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (38) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (39) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (40) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (41) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (42) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (43) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (44) 0.012 0.000074 328 (0) 72 (0) 71.2 (0) 72.9(0) 28 (1 or 2) 78.2 (1 or 2) 75.3 (1 or 2) 81 (1 or 2) (45) 0.0120.000074 328 (0) 72 (0) 71.2 (0) 72.9 (0) 28 (1 or 2) 78.2 (1 or 2) 75.3(1 or 2) 81 (1 or 2) (46) 0.015 0.000092 269 (0 or 1) 72.5 (0 or 1) 73.4(0 or 1) 74.4 (0 or 1) 87 (2) 68 (2) 69.6 (2) 71.3 (2) (47) 0.0150.000092 269 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 87 (2)68 (2) 69.6 (2) 71.3 (2) (48) 0.015 0.000092 269 (0 or 1) 72.5 (0 or 1)73.4 (0 or 1) 74.4 (0 or 1) 87 (2) 68 (2) 69.6 (2) 71.3 (2) (49) 0.0180.000114 320 (0) 72 (0) 71.1 (0) 72.8 (0) 36 (1 or 2) 77.3 (1 or 2) 74.8(1 or 2) 79.9 (1 or 2) (50) 0.018 0.000114 320 (0) 72 (0) 71.1 (0) 72.8(0) 36 (1 or 2) 77.3 (1 or 2) 74.8 (1 or 2) 79.9 (1 or 2) (51) 0.0180.000114 320 (0) 72 (0) 71.1 (0) 72.8 (0) 36 (1 or 2) 77.3 (1 or 2) 74.8(1 or 2) 79.9 (1 or 2) (52) 0.018 0.000114 320 (0) 72 (0) 71.1 (0) 72.8(0) 36 (1 or 2) 77.3 (1 or 2) 74.8 (1 or 2) 79.9 (1 or 2) (53) 0.0180.000114 320 (0) 72 (0) 71.1 (0) 72.8 (0) 36 (1 or 2) 77.3 (1 or 2) 74.8(1 or 2) 79.9 (1 or 2) (54) 0.018 0.000114 320 (0) 72 (0) 71.1 (0) 72.8(0) 36 (1 or 2) 77.3 (1 or 2) 74.8 (1 or 2) 79.9 (1 or 2) (55) 0.020.000122 130 (0) 70.4 (0) 69 (0) 71.7 (0) 226 (1 or 2) 73.7 (1 or 2)72.7 (1 or 2) 74.7 (1 or 2) (56) 0.02 0.000122 130 (0) 70.4 (0) 69 (0)71.7 (0) 226 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (57)0.021 0.000128 129 (0) 70.4 (0) 69 (0) 71.7 (0) 227 (1 or 2) 73.7 (1 or2) 72.7 (1 or 2) 74.7 (1 or 2) (58) 0.021 0.000128 129 (0) 70.4 (0) 69(0) 71.7 (0) 227 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (59)0.021 0.000128 129 (0) 70.4 (0) 69 (0) 71.7 (0) 227 (1 or 2) 73.7 (1 or2) 72.7 (1 or 2) 74.7 (1 or 2) (60) 0.021 0.000128 129 (0) 70.4 (0) 69(0) 71.7 (0) 227 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (61)0.021 0.000128 129 (0) 70.4 (0) 69 (0) 71.7 (0) 227 (1 or 2) 73.7 (1 or2) 72.7 (1 or 2) 74.7 (1 or 2) (62) 0.021 0.000128 129 (0) 70.4 (0) 69(0) 71.7 (0) 227 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (63)0.021 0.000128 129 (0) 70.4 (0) 69 (0) 71.7 (0) 227 (1 or 2) 73.7 (1 or2) 72.7 (1 or 2) 74.7 (1 or 2) (64) 0.021 0.000128 129 (0) 70.4 (0) 69(0) 71.7 (0) 227 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (65)0.021 0.000128 129 (0) 70.4 (0) 69 (0) 71.7 (0) 227 (1 or 2) 73.7 (1 or2) 72.7 (1 or 2) 74.7 (1 or 2) (66) 0.023 0.000143 120 (0) 70.2 (0) 68.8(0) 71.7 (0) 236 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.6 (1 or 2) (67)0.023 0.000143 120 (0) 70.2 (0) 68.8 (0) 71.7 (0) 236 (1 or 2) 73.7 (1or 2) 72.7 (1 or 2) 74.6 (1 or 2) (68) 0.023 0.000143 120 (0) 70.2 (0)68.8 (0) 71.7 (0) 236 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.6 (1 or 2)(69) 0.023 0.000143 120 (0) 70.2 (0) 68.8 (0) 71.7 (0) 236 (1 or 2) 73.7(1 or 2) 72.7 (1 or 2) 74.6 (1 or 2) (70) 0.023 0.000143 120 (0) 70.2(0) 68.8 (0) 71.7 (0) 236 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.6 (1or 2) (71) 0.024 0.000158 272 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.3(0 or 1) 84 (2) 68 (2) 69.7 (2) 71.3 (2) (72) 0.024 0.000168 273 (0or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 83 (2) 68 (2) 69.6 (2)71.3 (2) (73) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (74) 0.026 0.000184 121(0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (75) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235(1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (76) 0.026 0.000184121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or2) 74.6 (1 or 2) (77) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0)235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (78) 0.0260.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (79) 0.026 0.000184 121 (0) 70.3 (0) 68.9(0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (80)0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1or 2) 72.6 (1 or 2) 74.6 (1 or 2) (81) 0.026 0.000184 121 (0) 70.3 (0)68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(82) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6(1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (83) 0.026 0.000184 121 (0) 70.3(0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1or 2) (84) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (85) 0.026 0.000184 121 (0)70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (86) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (87) 0.026 0.000184 121(0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (88) 0.026 0.000184 121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235(1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (89) 0.026 0.000184121 (0) 70.3 (0) 68.9 (0) 71.7 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or2) 74.6 (1 or 2) (90) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0)236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (91) 0.0270.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (92) 0.027 0.000192 120 (0) 70.3 (0) 68.9(0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (93)0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1or 2) 72.6 (1 or 2) 74.6 (1 or 2) (94) 0.027 0.000192 120 (0) 70.3 (0)68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(95) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6(1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (96) 0.027 0.000192 120 (0) 70.3(0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1or 2) (97) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (98) 0.027 0.000192 120 (0)70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (99) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (100) 0.027 0.000192 120(0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (101) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0)236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (102) 0.0270.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (103) 0.027 0.000192 120 (0) 70.3 (0) 68.9(0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(104) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (105) 0.027 0.000192 120 (0)70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (106) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (107) 0.027 0.000192 120(0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (108) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0)236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (109) 0.0270.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (110) 0.027 0.000192 120 (0) 70.3 (0) 68.9(0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(111) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (112) 0.027 0.000192 120 (0)70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (113) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (114) 0.027 0.000192 120(0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (115) 0.027 0.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0)236 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (116) 0.0270.000192 120 (0) 70.3 (0) 68.9 (0) 71.7 (0) 236 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (117) 0.033 0.000214 127 (0) 70.4 (0) 69.1(0) 71.8 (0) 229 (1 or 2) 73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2)(118) 0.033 0.000214 127 (0) 70.4 (0) 69.1 (0) 71.8 (0) 229 (1 or 2)73.7 (1 or 2) 72.7 (1 or 2) 74.7 (1 or 2) (119) 0.033 0.000224 126 (0)70.4 (0) 69 (0) 71.8 (0) 230 (1 or 2) 73.7 (1 or 2) 72.6 (1 or 2) 74.7(1 or 2) (120) 0.034 0.000252 122 (0) 70.4 (0) 69 (0) 71.8 (0) 234 (1 or2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (121) 0.034 0.000252 122(0) 70.4 (0) 69 (0) 71.8 (0) 234 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (122) 0.034 0.000261 272 (0 or 1) 72.4 (0 or 1) 73.4 (0or 1) 74.3 (0 or 1) 84 (2) 68.1 (2) 69.7 (2) 71.4 (2) (123) 0.0340.000261 272 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 84 (2)68.1 (2) 69.7 (2) 71.4 (2) (124) 0.034 0.000261 272 (0 or 1) 72.4 (0or 1) 73.4 (0 or 1) 74.3 (0 or 1) 84 (2) 68.1 (2) 69.7 (2) 71.4 (2)(125) 0.034 0.000261 272 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0or 1) 84 (2) 68.1 (2) 69.7 (2) 71.4 (2) (126) 0.034 0.000263 121 (0)70.4 (0) 69 (0) 71.8 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (127) 0.034 0.000263 121 (0) 70.4 (0) 69 (0) 71.8 (0) 235 (1 or2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (128) 0.034 0.000263 121(0) 70.4 (0) 69 (0) 71.8 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (129) 0.034 0.000263 121 (0) 70.4 (0) 69 (0) 71.8 (0) 235(1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (130) 0.034 0.000263121 (0) 70.4 (0) 69 (0) 71.8 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or2) 74.6 (1 or 2) (131) 0.034 0.000263 121 (0) 70.4 (0) 69 (0) 71.8 (0)235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (132) 0.0340.000263 121 (0) 70.4 (0) 69 (0) 71.8 (0) 235 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (133) 0.034 0.000263 121 (0) 70.4 (0) 69 (0)71.8 (0) 235 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (134)0.037 0.000279 252 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.4 (0 or 1)104 (2) 68.6 (2) 70.1 (2) 71.6 (2) (135) 0.037 0.000279 252 (0 or 1)72.5 (0 or 1) 73.5 (0 or 1) 74.4 (0 or 1) 104 (2) 68.6 (2) 70.1 (2) 71.6(2) (136) 0.037 0.000279 252 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.4(0 or 1) 104 (2) 68.6 (2) 70.1 (2) 71.6 (2) (137) 0.037 0.000279 252 (0or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.4 (0 or 1) 104 (2) 68.6 (2) 70.1(2) 71.6 (2) (138) 0.037 0.000283 112 (0) 70.2 (0) 68.8 (0) 71.7 (0) 244(1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (139) 0.037 0.000283112 (0) 70.2 (0) 68.8 (0) 71.7 (0) 244 (1 or 2) 73.5 (1 or 2) 72.6 (1 or2) 74.5 (1 or 2) (140) 0.037 0.000283 112 (0) 70.2 (0) 68.8 (0) 71.7 (0)244 (1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (141) 0.0370.000283 112 (0) 70.2 (0) 68.8 (0) 71.7 (0) 244 (1 or 2) 73.5 (1 or 2)72.6 (1 or 2) 74.5 (1 or 2) (142) 0.037 0.000283 112 (0) 70.2 (0) 68.8(0) 71.7 (0) 244 (1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2)(143) 0.037 0.000283 112 (0) 70.2 (0) 68.8 (0) 71.7 (0) 244 (1 or 2)73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (144) 0.037 0.000283 112 (0)70.2 (0) 68.8 (0) 71.7 (0) 244 (1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5(1 or 2) (145) 0.038 0.000309 345 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 11 (2) 59.4 (2) 64.1 (2) 68.7 (2) (146) 0.038 0.000309 345(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 11 (2) 59.4 (2) 64.1(2) 68.7 (2) (147) 0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63(1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (148) 0.04 0.000320293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or2) 77.7 (1 or 2) (149) 0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0)63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (150) 0.040.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2)73.8 (1 or 2) 77.7 (1 or 2) (151) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (152)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (153) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (154)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (155) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (156)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (157) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (158)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (159) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (160)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (161) 0.04 0.000320 293 (0) 71.8 (0) 70.9(0) 72.7 (0) 63 (1 or 2) 75.7 (1 or 2) 73.8 (1 or 2) 77.7 (1 or 2) (162)0.04 0.000320 293 (0) 71.8 (0) 70.9 (0) 72.7 (0) 63 (1 or 2) 75.7 (1 or2) 73.8 (1 or 2) 77.7 (1 or 2) (163) 0.041 0.000335 269 (0 or 1) 72.4 (0or 1) 73.4 (0 or 1) 74.3 (0 or 1) 87 (2) 68.2 (2) 69.9 (2) 71.5 (2)(164) 0.041 0.000335 269 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0or 1) 87 (2) 68.2 (2) 69.9 (2) 71.5 (2) (165) 0.041 0.000335 269 (0or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 87 (2) 68.2 (2) 69.9 (2)71.5 (2) (166) 0.041 0.000338 255 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1)74.4 (0 or 1) 101 (2) 68.6 (2) 70.1 (2) 71.6 (2) (167) 0.041 0.000338255 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.4 (0 or 1) 101 (2) 68.6 (2)70.1 (2) 71.6 (2) (168) 0.041 0.000338 255 (0 or 1) 72.5 (0 or 1) 73.5(0 or 1) 74.4 (0 or 1) 101 (2) 68.6 (2) 70.1 (2) 71.6 (2) (169) 0.0410.000338 255 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.4 (0 or 1) 101 (2)68.6 (2) 70.1 (2) 71.6 (2) (170) 0.047 0.000390 260 (0 or 1) 72.5 (0or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96 (2) 68.5 (2) 70 (2) 71.6 (2) (171)0.047 0.000390 260 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96(2) 68.5 (2) 70 (2) 71.6 (2) (172) 0.047 0.000390 260 (0 or 1) 72.5 (0or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96 (2) 68.5 (2) 70 (2) 71.6 (2) (173)0.047 0.000390 260 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96(2) 68.5 (2) 70 (2) 71.6 (2) (174) 0.047 0.000390 260 (0 or 1) 72.5 (0or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96 (2) 68.5 (2) 70 (2) 71.6 (2) (175)0.047 0.000390 260 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96(2) 68.5 (2) 70 (2) 71.6 (2) (176) 0.047 0.000390 260 (0 or 1) 72.5 (0or 1) 73.4 (0 or 1) 74.4 (0 or 1) 96 (2) 68.5 (2) 70 (2) 71.6 (2) (177)0.047 0.000390 113 (0) 70.3 (0) 68.8 (0) 71.8 (0) 243 (1 or 2) 73.5 (1or 2) 72.5 (1 or 2) 74.5 (1 or 2) (178) 0.047 0.000390 113 (0) 70.3 (0)68.8 (0) 71.8 (0) 243 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(179) 0.047 0.000390 113 (0) 70.3 (0) 68.8 (0) 71.8 (0) 243 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (180) 0.047 0.000390 113 (0)70.3 (0) 68.8 (0) 71.8 (0) 243 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (181) 0.049 0.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (182) 0.049 0.000422 119(0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.5 (1 or 2) (183) 0.049 0.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0) 237(1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (184) 0.049 0.000422119 (0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or2) 74.5 (1 or 2) (185) 0.049 0.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0)237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (186) 0.0490.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.5 (1 or 2) (187) 0.049 0.000422 119 (0) 70.4 (0) 69 (0)71.8 (0) 237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (188)0.049 0.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6 (1 or2) 72.6 (1 or 2) 74.5 (1 or 2) (189) 0.049 0.000422 119 (0) 70.4 (0) 69(0) 71.8 (0) 237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2)(190) 0.049 0.000422 119 (0) 70.4 (0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6(1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (191) 0.049 0.000422 119 (0) 70.4(0) 69 (0) 71.8 (0) 237 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.5 (1 or2) (192) 0.051 0.000440 275 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0or 1) 81 (2) 68.1 (2) 69.8 (2) 71.5 (2) (193) 0.051 0.000440 118 (0)70.4 (0) 69 (0) 71.8 (0) 238 (1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5(1 or 2) (194) 0.051 0.000440 118 (0) 70.4 (0) 69 (0) 71.8 (0) 238 (1 or2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (195) 0.051 0.000440 118(0) 70.4 (0) 69 (0) 71.8 (0) 238 (1 or 2) 73.5 (1 or 2) 72.6 (1 or 2)74.5 (1 or 2) (196) 0.051 0.000440 118 (0) 70.4 (0) 69 (0) 71.8 (0) 238(1 or 2) 73.5 (1 or 2) 72.6 (1 or 2) 74.5 (1 or 2) (197) 0.053 0.000456344 (0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 12 (2) 60.2 (2)64.6 (2) 69.1 (2) (198) 0.053 0.000456 344 (0 or 1) 72 (0 or 1) 72.8 (0or 1) 73.6 (0 or 1) 12 (2) 60.2 (2) 64.6 (2) 69.1 (2) (199) 0.0540.000463 276 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0 or 1) 80 (2)68.1 (2) 69.8 (2) 71.5 (2) (200) 0.056 0.000478 255 (0 or 1) 72.5 (0or 1) 73.4 (0 or 1) 74.4 (0 or 1) 101 (2) 68.6 (2) 70.2 (2) 71.7 (2)(201) 0.056 0.000478 255 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0or 1) 101 (2) 68.6 (2) 70.2 (2) 71.7 (2) (202) 0.056 0.000478 255 (0or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 101 (2) 68.6 (2) 70.2(2) 71.7 (2) (203) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227(1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (204) 0.057 0.000503129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or2) 74.6 (1 or 2) (205) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0)227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (206) 0.0570.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (207) 0.057 0.000503 129 (0) 70.6 (0) 69.2(0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(208) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (209) 0.057 0.000503 129 (0)70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (210) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (211) 0.057 0.000503 129(0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (212) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0)227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (213) 0.0570.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (214) 0.057 0.000503 129 (0) 70.6 (0) 69.2(0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(215) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (216) 0.057 0.000503 129 (0)70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (217) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (218) 0.057 0.000503 129(0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (219) 0.057 0.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0)227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (220) 0.0570.000503 129 (0) 70.6 (0) 69.2 (0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (221) 0.057 0.000503 129 (0) 70.6 (0) 69.2(0) 71.9 (0) 227 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(222) 0.057 0.000510 256 (0 or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0or 1) 100 (2) 68.6 (2) 70.2 (2) 71.7 (2) (223) 0.057 0.000510 256 (0or 1) 72.5 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 100 (2) 68.6 (2) 70.2(2) 71.7 (2) (224) 0.057 0.000510 256 (0 or 1) 72.5 (0 or 1) 73.4 (0or 1) 74.4 (0 or 1) 100 (2) 68.6 (2) 70.2 (2) 71.7 (2) (225) 0.0590.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (226) 0.059 0.000528 128 (0) 70.6 (0) 69.2(0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(227) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (228) 0.059 0.000528 128 (0)70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (229) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (230) 0.059 0.000528 128(0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (231) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0)228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (232) 0.0590.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (233) 0.059 0.000528 128 (0) 70.6 (0) 69.2(0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(234) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (235) 0.059 0.000528 128 (0)70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (236) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (237) 0.059 0.000528 128(0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (238) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0)228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (239) 0.0590.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (240) 0.059 0.000528 128 (0) 70.6 (0) 69.2(0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(241) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (242) 0.059 0.000528 128 (0)70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (243) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (244) 0.059 0.000528 128(0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (245) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0)228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (246) 0.0590.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (247) 0.059 0.000528 128 (0) 70.6 (0) 69.2(0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(248) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (249) 0.059 0.000528 128 (0)70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (250) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (251) 0.059 0.000528 128(0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (252) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0)228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (253) 0.0590.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2)72.6 (1 or 2) 74.6 (1 or 2) (254) 0.059 0.000528 128 (0) 70.6 (0) 69.2(0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2)(255) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2)73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (256) 0.059 0.000528 128 (0)70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6(1 or 2) (257) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (258) 0.059 0.000528 128(0) 70.6 (0) 69.2 (0) 71.9 (0) 228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2)74.6 (1 or 2) (259) 0.059 0.000528 128 (0) 70.6 (0) 69.2 (0) 71.9 (0)228 (1 or 2) 73.6 (1 or 2) 72.6 (1 or 2) 74.6 (1 or 2) (260) 0.0650.000568 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (261) 0.065 0.000568 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(262) 0.066 0.000594 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (263) 0.066 0.000595 273 (0or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0 or 1) 83 (2) 68.2 (2) 69.9 (2)71.6 (2) (264) 0.066 0.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (265) 0.066 0.000604 119(0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (266) 0.066 0.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0) 237(1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (267) 0.066 0.000604119 (0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or2) 74.5 (1 or 2) (268) 0.066 0.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (269) 0.0660.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (270) 0.066 0.000604 119 (0) 70.5 (0) 69 (0)71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (271)0.066 0.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or2) 72.5 (1 or 2) 74.5 (1 or 2) (272) 0.066 0.000604 119 (0) 70.5 (0) 69(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(273) 0.066 0.000604 119 (0) 70.5 (0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5(1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (274) 0.066 0.000604 119 (0) 70.5(0) 69 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or2) (275) 0.066 0.000615 259 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0or 1) 97 (2) 68.6 (2) 70.1 (2) 71.7 (2) (276) 0.066 0.000615 259 (0or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 97 (2) 68.6 (2) 70.1 (2)71.7 (2) (277) 0.066 0.000615 259 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1)74.3 (0 or 1) 97 (2) 68.6 (2) 70.1 (2) 71.7 (2) (278) 0.071 0.000660 263(0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 93 (2) 68.5 (2) 70.1(2) 71.7 (2) (279) 0.071 0.000660 263 (0 or 1) 72.4 (0 or 1) 73.4 (0or 1) 74.3 (0 or 1) 93 (2) 68.5 (2) 70.1 (2) 71.7 (2) (280) 0.0710.000660 263 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 93 (2)68.5 (2) 70.1 (2) 71.7 (2) (281) 0.071 0.000660 263 (0 or 1) 72.4 (0or 1) 73.4 (0 or 1) 74.3 (0 or 1) 93 (2) 68.5 (2) 70.1 (2) 71.7 (2)(282) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (283) 0.072 0.000686 341 (0or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2)69.7 (2) (284) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (285) 0.072 0.000686 341(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7(2) 69.7 (2) (286) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (287) 0.072 0.000686 341(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7(2) 69.7 (2) (288) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (289) 0.072 0.000686 341(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7(2) 69.7 (2) (290) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (291) 0.072 0.000686 341(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7(2) 69.7 (2) (292) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (293) 0.072 0.000686 341(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 15 (2) 61.7 (2) 65.7(2) 69.7 (2) (294) 0.072 0.000686 341 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 15 (2) 61.7 (2) 65.7 (2) 69.7 (2) (295) 0.072 0.000704 264(0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0 or 1) 92 (2) 68.5 (2) 70.1(2) 71.7 (2) (296) 0.072 0.000704 264 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.3 (0 or 1) 92 (2) 68.5 (2) 70.1 (2) 71.7 (2) (297) 0.0720.000704 264 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0 or 1) 92 (2)68.5 (2) 70.1 (2) 71.7 (2) (298) 0.072 0.000704 264 (0 or 1) 72.4 (0or 1) 73.3 (0 or 1) 74.3 (0 or 1) 92 (2) 68.5 (2) 70.1 (2) 71.7 (2)(299) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (300) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (301) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (302) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (303) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (304) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (305) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(306) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (307) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (308) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (309) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (310) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (311) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (312) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(313) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (314) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (315) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (316) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (317) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (318) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (319) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(320) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (321) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (322) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (323) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (324) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (325) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (326) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(327) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (328) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (329) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (330) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (331) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (332) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (333) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) 2)(334) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (335) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (336) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (337) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (338) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (339) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (340) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(341) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (342) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (343) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (344) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (345) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (346) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (347) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(348) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (349) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (350) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (351) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (352) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (353) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (354) 0.076 0.000746 120 (0) 70.5 (0) 69.1(0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(355) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (356) 0.076 0.000746 120 (0)70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (357) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (358) 0.076 0.000746 120(0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (359) 0.076 0.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0)236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (360) 0.0760.000746 120 (0) 70.5 (0) 69.1 (0) 71.9 (0) 236 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (361) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(362) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (363) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (364) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (365) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (366) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (367) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (368) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(369) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (370) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (371) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (372) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (373) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (374) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (375) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(376) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (377) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (378) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (379) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (380) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (381) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (382) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(383) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (384) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (385) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (386) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (387) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (388) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (389) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(390) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (391) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (392) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (393) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (394) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (395) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (396) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(397) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (398) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (399) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (400) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (401) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (402) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (403) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(404) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (405) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (406) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (407) 0.079 0.000779 119(0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (408) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0)237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (409) 0.0790.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (410) 0.079 0.000779 119 (0) 70.5 (0) 69.1(0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(411) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (412) 0.079 0.000779 119 (0)70.5 (0) 69.1 (0) 71.9 (0) 237 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (413) 0.079 0.000779 119 (0) 70.5 (0) 69.1 (0) 71.9 (0) 237 (1or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (414) 0.079 0.000779 237(0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.5 (0 or 1) 119 (2) 69.1 (2) 70.5(2) 71.9 (2) (415) 0.079 0.000779 237 (0 or 1) 72.5 (0 or 1) 73.5 (0or 1) 74.5 (0 or 1) 119 (2) 69.1 (2) 70.5 (2) 71.9 (2) (416) 0.0790.000779 237 (0 or 1) 72.5 (0 or 1) 73.5 (0 or 1) 74.5 (0 or 1) 119 (2)69.1 (2) 70.5 (2) 71.9 (2) (417) 0.079 0.000779 237 (0 or 1) 72.5 (0or 1) 73.5 (0 or 1) 74.5 (0 or 1) 119 (2) 69.1 (2) 70.5 (2) 71.9 (2)(418) 0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5(1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (419) 0.084 0.000844 126 (0) 70.6(0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or2) (420) 0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (421) 0.084 0.000844 126 (0)70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6(1 or 2) (422) 0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (423) 0.084 0.000844 126(0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.6 (1 or 2) (424) 0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230(1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (425) 0.084 0.000844126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or2) 74.6 (1 or 2) (426) 0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0)230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (427) 0.0840.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.6 (1 or 2) (428) 0.084 0.000844 126 (0) 70.6 (0) 69.2(0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2) (429)0.084 0.000844 126 (0) 70.6 (0) 69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or2) 72.5 (1 or 2) 74.6 (1 or 2) (430) 0.084 0.000844 126 (0) 70.6 (0)69.2 (0) 72 (0) 230 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.6 (1 or 2)(431) 0.085 0.000857 259 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0or 1) 97 (2) 68.7 (2) 70.2 (2) 71.8 (2) (432) 0.085 0.000857 340 (0or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (433) 0.085 0.000857 340 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2) 69.9 (2) (434) 0.085 0.000857 340(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (435) 0.085 0.000857 340 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2) 69.9 (2) (436) 0.085 0.000857 340(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (437) 0.085 0.000857 340 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2) 69.9 (2) (438) 0.085 0.000857 340(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (439) 0.085 0.000857 340 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2) 69.9 (2) (440) 0.085 0.000857 340(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (441) 0.085 0.000857 340 (0 or 1) 72 (0 or 1) 72.8 (0 or 1)73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2) 69.9 (2) (442) 0.085 0.000857 340(0 or 1) 72 (0 or 1) 72.8 (0 or 1) 73.6 (0 or 1) 16 (2) 62.2 (2) 66 (2)69.9 (2) (443) 0.088 0.000880 252 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1)74.4 (0 or 1) 104 (2) 68.8 (2) 70.3 (2) 71.8 (2) (444) 0.088 0.000880252 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 104 (2) 68.8 (2)70.3 (2) 71.8 (2) (445) 0.088 0.000880 252 (0 or 1) 72.4 (0 or 1) 73.4(0 or 1) 74.4 (0 or 1) 104 (2) 68.8 (2) 70.3 (2) 71.8 (2) (446) 0.0880.000880 252 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 104 (2)68.8 (2) 70.3 (2) 71.8 (2) (447) 0.089 0.000884 125 (0) 70.6 (0) 69.2(0) 72 (0) 231 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (448)0.089 0.000884 125 (0) 70.6 (0) 69.2 (0) 72 (0) 231 (1 or 2) 73.5 (1 or2) 72.5 (1 or 2) 74.5 (1 or 2) (449) 0.089 0.000884 125 (0) 70.6 (0)69.2 (0) 72 (0) 231 (1 or 2) 3.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(450) 0.089 0.000884 125 (0) 70.6 (0) 69.2 (0) 72 (0) 231 (1 or 2) 73.5(1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (451) 0.089 0.000884 125 (0) 70.6(0) 69.2 (0) 72 (0) 231 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or2) (452) 0.089 0.000884 258 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0or 1) 98 (2) 68.7 (2) 70.2 (2) 71.8 (2) (453) 0.089 0.000884 258 (0or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 98 (2) 68.7 (2) 70.2 (2)71.8 (2) (454) 0.089 0.000884 258 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1)74.3 (0 or 1) 98 (2) 68.7 (2) 70.2 (2) 71.8 (2) (455) 0.089 0.000884 258(0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.3 (0 or 1) 98 (2) 68.7 (2) 70.2(2) 71.8 (2) (456) 0.089 0.000887 272 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.2 (0 or 1) 84 (2) 68.3 (2) 70 (2) 71.7 (2) (457) 0.089 0.000887272 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0 or 1) 84 (2) 68.3 (2)70 (2) 71.7 (2) (458) 0.089 0.000887 272 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.2 (0 or 1) 84 (2) 68.3 (2) 70 (2) 71.7 (2) (459) 0.089 0.000887272 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0 or 1) 84 (2) 68.3 (2)70 (2) 71.7 (2) (460) 0.089 0.000887 272 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.2 (0 or 1) 84 (2) 68.3 (2) 70 (2) 71.7 (2) (461) 0.089 0.000887272 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.2 (0 or 1) 84 (2) 68.3 (2)70 (2) 71.7 (2) (462) 0.089 0.000887 272 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.2 (0 or 1) 84 (2) 68.3 (2) 70 (2) 71.7 (2) (463) 0.094 0.000973312 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 44 (2) 66.5 (2)68.8 (2) 71.1 (2) (464) 0.094 0.000973 312 (0 or 1) 72.2 (0 or 1) 73 (0or 1) 73.9 (0 or 1) 44 (2) 66.5 (2) 68.8 (2) 71.1 (2) (465) 0.0940.000973 312 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 44 (2)66.5 (2) 68.8 (2) 71.1 (2) (466) 0.094 0.000973 312 (0 or 1) 72.2 (0or 1) 73 (0 or 1) 73.9 (0 or 1) 44 (2) 66.5 (2) 68.8 (2) 71.1 (2) (467)0.094 0.000973 312 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 44(2) 66.5 (2) 68.8 (2) 71.1 (2) (468) 0.094 0.000973 312 (0 or 1) 72.2 (0or 1) 73 (0 or 1) 73.9 (0 or 1) 44 (2) 66.5 (2) 68.8 (2) 71.1 (2) (469)0.094 0.000973 312 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 44(2) 66.5 (2) 68.8 (2) 71.1 (2) (470) 0.094 0.000973 312 (0 or 1) 72.2 (0or 1) 73 (0 or 1) 73.9 (0 or 1) 44 (2) 66.5 (2) 68.8 (2) 71.1 (2) (471)0.094 0.000973 312 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 44(2) 66.5 (2) 68.8 (2) 71.1 (2) (472) 0.095 0.000990 121 (0) 70.6 (0)69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(473) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5(1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (474) 0.095 0.000990 121 (0) 70.6(0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or2) (475) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (476) 0.095 0.000990 121 (0)70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (477) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (478) 0.095 0.000990 121(0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2)74.5 (1 or 2) (479) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235(1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (480) 0.095 0.000990121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or2) 74.5 (1 or 2) (481) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0)235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (482) 0.0950.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2)72.5 (1 or 2) 74.5 (1 or 2) (483) 0.095 0.000990 121 (0) 70.6 (0) 69.2(0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (484)0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or2) 72.5 (1 or 2) 74.5 (1 or 2) (485) 0.095 0.000990 121 (0) 70.6 (0)69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2)(486) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5(1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (487) 0.095 0.000990 121 (0) 70.6(0) 69.2 (0) 72 (0) 235 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or2) (488) 0.095 0.000990 121 (0) 70.6 (0) 69.2 (0) 72 (0) 235 (1 or 2)73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (489) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (490) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (491) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (492) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (493) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (494) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (495) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (496) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (497) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (498) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (499) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (500) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (501) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (502) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (503) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (504) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (505) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5(1 or 2) (506) 0.1 0.001035 120 (0) 70.6 (0) 69.2 (0) 72 (0) 236 (1 or2) 73.5 (1 or 2) 72.5 (1 or 2) 74.5 (1 or 2) (507) 0.1 0.001035 120 (0)70.6 (0) 69.2 (0) 72 (0) 236 (1 or 2) 73.5 (1 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(554) 0.108 0.001122 327 (0)72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9(1 or 2) (555) 0.108 0.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (556) 0.108 0.001122 327(0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2)79.9 (1 or 2) (557) 0.108 0.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29(1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (558) 0.108 0.001122327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or2) 79.9 (1 or 2) (559) 0.108 0.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0)29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (560) 0.1080.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2)74.2 (1 or 2) 79.9 (1 or 2) (561) 0.108 0.001122 327 (0) 72.1 (0) 71.3(0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (562)0.108 0.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or2) 74.2 (1 or 2) 79.9 (1 or 2) (563) 0.108 0.001122 327 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(0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or2) 79.9 (1 or 2) (702) 0.108 0.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0)29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (703) 0.1080.001122 327 (0) 72.1 (0) 71.3 (0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2)74.2 (1 or 2) 79.9 (1 or 2) (704) 0.108 0.001122 327 (0) 72.1 (0) 71.3(0) 72.9 (0) 29 (1 or 2) 77.1 (1 or 2) 74.2 (1 or 2) 79.9 (1 or 2) (705)0.11 0.001139 111 (0) 70.5 (0) 69 (0) 71.9 (0) 245 (1 or 2) 73.4 (1 or2) 72.4 (1 or 2) 74.4 (1 or 2) (706) 0.11 0.001139 111 (0) 70.5 (0) 69(0) 71.9 (0) 245 (1 or 2) 73.4 (1 or 2) 72.4 (1 or 2) 74.4 (1 or 2)(707) 0.11 0.001139 111 (0) 70.5 (0) 69 (0) 71.9 (0) 245 (1 or 2) 73.4(1 or 2) 72.4 (1 or 2) 74.4 (1 or 2) (708) 0.11 0.001139 111 (0) 70.5(0) 69 (0) 71.9 (0) 245 (1 or 2) 73.4 (1 or 2) 72.4 (1 or 2) 74.4 (1 or2) (709) 0.11 0.001139 111 (0) 70.5 (0) 69 (0) 71.9 (0) 245 (1 or 2)73.4 (1 or 2) 72.4 (1 or 2) 74.4 (1 or 2) (710) 0.11 0.001139 111 (0)70.5 (0) 69 (0) 71.9 (0) 245 (1 or 2) 73.4 (1 or 2) 72.4 (1 or 2) 74.4(1 or 2) (711) 0.11 0.001139 111 (0) 70.5 (0) 69 (0) 71.9 (0) 245 (1 or2) 73.4 (1 or 2) 72.4 (1 or 2) 74.4 (1 or 2) (712) 0.11 0.001139 111 (0)70.5 (0) 69 (0) 71.9 (0) 245 (1 or 2) 73.4 (1 or 2) 72.4 (1 or 2) 74.4(1 or 2) (713) 0.11 0.001139 245 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1)74.4 (0 or 1) 111 (2) 69 (2) 70.5 (2) 71.9 (2) (714) 0.11 0.001139 245(0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 111 (2) 69 (2) 70.5(2) 71.9 (2) (715) 0.11 0.001139 245 (0 or 1) 72.4 (0 or 1) 73.4 (0or 1) 74.4 (0 or 1) 111 (2) 69 (2) 70.5 (2) 71.9 (2) (716) 0.11 0.001139245 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 111 (2) 69 (2)70.5 (2) 71.9 (2) (717) 0.11 0.001139 245 (0 or 1) 72.4 (0 or 1) 73.4 (0or 1) 74.4 (0 or 1) 111 (2) 69 (2) 70.5 (2) 71.9 (2) (718) 0.11 0.001139245 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 111 (2) 69 (2)70.5 (2) 71.9 (2) (719) 0.11 0.001139 245 (0 or 1) 72.4 (0 or 1) 73.4 (0or 1) 74.4 (0 or 1) 111 (2) 69 (2) 70.5 (2) 71.9 (2) (720) 0.11 0.001139245 (0 or 1) 72.4 (0 or 1) 73.4 (0 or 1) 74.4 (0 or 1) 111 (2) 69 (2)70.5 (2) 71.9 (2) (721) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (722) 0.112 0.001164310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69(2) 71.2 (2) (723) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (724) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (725) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (726) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (727) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (728) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (729) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (730) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (731) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (732) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (733) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (734) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (735) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (736) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (737) 0.112 0.001164 310 (0 or 1) 72.2 (0 or 1) 73 (0 or 1)73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2) 71.2 (2) (738) 0.112 0.001164 310(0 or 1) 72.2 (0 or 1) 73 (0 or 1) 73.9 (0 or 1) 46 (2) 66.7 (2) 69 (2)71.2 (2) (739) 0.112 0.001170 267 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1)74.2 (0 or 1) 89 (2) 68.5 (2) 70.1 (2) 71.8 (2) (740) 0.113 0.001186 345(0 or 1) 71.9 (0 or 1) 72.7 (0 or 1) 73.6 (0 or 1) 11 (2) 60.2 (2) 64.9(2) 69.5 (2) (741) 0.113 0.001186 345 (0 or 1) 71.9 (0 or 1) 72.7 (0or 1) 73.6 (0 or 1) 11 (2) 60.2 (2) 64.9 (2) 69.5 (2) (742) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (743) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (744) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (745) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (746) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (747) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (748) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (749) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (750) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (751) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (752) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (753) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (754) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (755) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (756) 0.1150.001208 319 (0) 72 (0) 71.2 (0) 72.9 (0) 37 (1 or 2) 76.5 (1 or 2) 74(1 or 2) 79 (1 or 2) (757) 0.115 0.001208 319 (0) 72 (0) 71.2 (0) 72.9(0) 37 (1 or 2) 76.5 (1 or 2) 74 (1 or 2) 79 (1 or 2) (758) 0.1160.001227 260 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0 or 1) 96 (2)68.7 (2) 70.3 (2) 71.8 (2) (759) 0.116 0.001227 260 (0 or 1) 72.4 (0or 1) 73.3 (0 or 1) 74.3 (0 or 1) 96 (2) 68.7 (2) 70.3 (2) 71.8 (2)(760) 0.116 0.001227 260 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0or 1) 96 (2) 68.7 (2) 70.3 (2) 71.8 (2) (761) 0.116 0.001227 260 (0or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0 or 1) 96 (2) 68.7 (2) 70.3 (2)71.8 (2) (762) 0.116 0.001227 260 (0 or 1) 72.4 (0 or 1) 73.3 (0 or 1)74.3 (0 or 1) 96 (2) 68.7 (2) 70.3 (2) 71.8 (2) (763) 0.116 0.001227 260(0 or 1) 72.4 (0 or 1) 73.3 (0 or 1) 74.3 (0 or 1) 96 (2) 68.7 (2) 70.3(2) 71.8 (2) (764) 0.116 0.001227 260 (0 or 1) 72.4 (0 or 1) 73.3 (0or 1) 74.3 (0 or 1) 96 (2) 68.7 (2) 70.3 (2) 71.8 (2)

As seen in Table 8, each of the 764 haplotypes shows a correlation withan individual's age of onset of AD. When p-values were adjusted formultiple comparisons, haplotypes (1)-(45) showed the strongestcorrelation. The Least Square Mean of Age of Onset column indicates theaverage age of onset of AD in individuals, in this cohort, having (a)one copy or two copies, or zero copies, or (b) zero copies or one copy,or two copies of a particular haplotype.

In view of the above, it will be seen that the several advantages of theinvention are achieved and other advantageous results attained. Asvarious changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description and shown in theaccompanying drawings shall be interpreted as illustrative and not in alimiting sense.

All references cited in this specification, including patents and patentapplications, are hereby incorporated in their entirety by reference.The discussion of references herein is intended merely to summarize theassertions made by their authors and no admission is made that anyreference constitutes prior art. Applicants reserve the right tochallenge the accuracy and pertinence of the cited references.

1. A method for determining whether an individual has an age of onsetmarker I or an age of onset marker II, the method comprising:determining whether the individual has (a) one copy or two copies, orzero copies of any of (i) haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii) a linkedhaplotype for any of haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy, or two copies of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, (ii) a linked haplotype for any of haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, wherein the polymorphic sites(PSs) in haplotypes (1)-(764) in Table 1 correspond to the followingnucleotide positions in SEQ ID NO:1: PS1, 1703; PS2, 12203; PS3, 18873;PS4, 23591; PS5, 25782; PS6, 28361; PS7, 28771; PS8, 28845; PS9, 28893;PS11, 32494; PS12, 32626; PS13, 43101; and PS14, 43168, wherein theindividual has an age of onset marker I if the individual has (a) onecopy or two copies of any of (i) haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii)a linked haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, and(iii) a substitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, (ii) a linkedhaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, and the individual has an age of onset marker II if theindividual has (a) zero copies of any of (i) haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) two copies of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, (ii) a linkedhaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable
 1. 2. The method of claim 1, wherein the determining stepcomprises obtaining the individual's genotype for each PS in the set ofPSs comprising any of (a) haplotypes (1)-(764) in Table 1, (b) a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, and (c) asubstitute haplotype for any of haplotypes (1)-(764) in Table 1, andusing the results of the obtaining step to identify the pair ofhaplotypes for the set of PSs.
 3. The method of claim 2, wherein theindividual's genotype for the set of PSs is obtained by any of (a) aprimer extension assay; (b) an allele-specific PCR assay; (c) a nucleicacid amplification assay; (d) a hybridization assay; (e) amismatch-detection assay; (f) an enzymatic nucleic acid cleavage assay;and (g) a sequencing assay.
 4. The method of claim 1, wherein thedetermining step comprises consulting a data repository that providesinformation on the individual's copy number for any of (a) haplotypes(1)-(764) in Table 1, (b) a linked haplotype for any of haplotypes(1)-(764) in Table 1, and (c) a substitute haplotype for any ofhaplotypes (1)-(764) in Table
 1. 5. The method of claim 4, wherein thedata repository is the individual's medical records or a medical datacard.
 6. The method of claim 1, wherein the method comprises determiningwhether an individual has one copy or two copies, or zero copies of anyof (a) haplotype (147) in Table 1, (b) a linked haplotype for haplotype(147) in Table 1, and (c) a substitute haplotype for haplotype (147) inTable
 1. 7. The method of claim 6, wherein the method comprisesdetermining whether an individual has one copy or two copies, or zerocopies of haplotype (147) in Table
 1. 8. The method of claim 1, whereinthe linkage disequilibrium between the linked haplotype and at least oneof haplotypes (1)-(764) in Table 1 has a delta squared value selectedfrom the group consisting of at least 0.75, at least 0.80, at least0.85, at least 0.90, at least 0.95, and 1.0.
 9. The method of claim 8,wherein the linked haplotype is for haplotype (147) in Table 1 and thelinkage disequilibrium between the linked haplotype and haplotype (147)in Table 1 has a delta squared value of at least 0.95.
 10. The method ofclaim 1, wherein the linkage disequilibrium between the allele at asubstituting PS in the substitute haplotype and the allele at asubstituted PS in any of haplotypes (1)-(764) in Table 1 has a deltasquared value selected from the group consisting of at least 0.75, least0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0.
 11. Themethod of claim 10, wherein the linkage disequilibrium between theallele at a substituting PS and the allele at a substituted PS inhaplotype (147) in Table 1 has a delta squared value of at least 0.95.12. The method of claim 1, wherein the individual is Caucasian.
 13. Amethod for assigning an individual to a first age of onset marker groupor a second age of onset marker group, the method comprising:determining whether the individual has (a) one copy or two copies, orzero copies of any of (i) haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, (ii) a linkedhaplotype for any of haplotypes (1)-(45), (49)-(70), (73)-(121),(126)-(133), (138)-(144), (147)-(162), (177)-(191), (193)-(195),(203)-221), (225)-(262), (264)-(274), (299)-(413), (418)-(430),(447)-(451), (472)-(712), and (742)-(757) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (1)-(45), (49)-(70),(73)-(121), (126)-(133), (138)-(144), (147)-(162), (177)-(191),(193)-(195), (203)-221), (225)-(262), (264)-(274), (299)-(413),(418)-(430), (447)-(451), (472)-(712), and (742)-(757) in Table 1, or(b) zero copies or one copy, or two copies of any of (i) haplotypes(46)-(48), (71), (72), (122)-(125), (134)-(137), (145), (146),(163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, (ii) a linked haplotype for any of haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, and (iii) asubstitute haplotype for any of haplotypes (46)-(48), (71), (72),(122)-(125), (134)-(137), (145), (146), (163)-(176), (192), (196)-(202),(222)-(224), (263), (275)-(298), (414)-(417), (431)-(446), (452)-(471),(713)-(741), and (758)-(764) in Table 1, wherein the polymorphic sites(PSs) in haplotypes (1)-(764) in Table 1 correspond to the followingnucleotide positions in SEQ ID NO:1: PS1, 1703; PS2, 12203; PS3, 18873;PS4, 23591; PS5, 25782; PS6, 28361; PS7, 28771; PS8, 28845; PS9, 28893;PS11, 32494; PS12, 32626; PS13, 43101; and PS14, 43168; and assigningthe individual to the first age of onset marker group if the individualhas (a) one copy or two copies of any of (i) haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) zero copies one copy of any of (i) haplotypes (46)-(48),(71), (72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, (ii) a linkedhaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable 1, and assigning the individual to the second age of onset markergroup if the individual has (a) zero copies of any of (i) haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, (ii) a linked haplotype for any of haplotypes (1)-(45),(49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, and (iii) a substitute haplotype for any of haplotypes(1)-(45), (49)-(70), (73)-(121), (126)-(133), (138)-(144), (147)-(162),(177)-(191), (193)-(195), (203)-221), (225)-(262), (264)-(274),(299)-(413), (418)-(430), (447)-(451), (472)-(712), and (742)-(757) inTable 1, or (b) two copies of any of (i) haplotypes (46)-(48), (71),(72), (122)-(125), (134)-(137), (145), (146), (163)-(176), (192),(196)-(202), (222)-(224), (263), (275)-(298), (414)-(417), (431)-(446),(452)-(471), (713)-(741), and (758)-(764) in Table 1, (ii) a linkedhaplotype for any of haplotypes (46)-(48), (71), (72), (122)-(125),(134)-(137), (145), (146), (163)-(176), (192), (196)-(202), (222)-(224),(263), (275)-(298), (414)-(417), (431)-(446), (452)-(471), (713)-(741),and (758)-(764) in Table 1, and (iii) a substitute haplotype for any ofhaplotypes (46)-(48), (71), (72), (122)-(125), (134)-(137), (145),(146), (163)-(176), (192), (196)-(202), (222)-(224), (263), (275)-(298),(414)-(417), (431)-(446), (452)-(471), (713)-(741), and (758)-(764) inTable
 1. 14. The method of claim 13, wherein the determining stepcomprises obtaining the individual's genotype for each PS in the set ofPSs comprising any of (a) haplotypes (1)-(764) in Table 1, (b) a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, and (c) asubstitute haplotype for any of haplotypes (1)-(764) in Table 1, andusing the results of the obtaining step to identify the pair ofhaplotypes for the set of PSs.
 15. The method of claim 14, wherein theindividual's genotype for the set of PSs is obtained by any of (a) aprimer extension assay; (b) an allele-specific PCR assay; (c) a nucleicacid amplification assay; (d) a hybridization assay; (e) amismatch-detection assay; (f) an enzymatic nucleic acid cleavage assay;and (g) a sequencing assay.
 16. The method of claim 13, wherein thedetermining step comprises consulting a data repository that providesinformation on the individual's copy number for any of (a) haplotypes(1)-(764) in Table 1, (b) a linked haplotype for any of haplotypes(1)-(764) in Table 1, and (c) a substitute haplotype for any ofhaplotypes (1)-(764) in Table
 1. 17. The method of claim 16, wherein thedata repository is the individual's medical records or a medical datacard.
 18. The method of claim 13, wherein the method comprises:determining whether the individual has one copy or two copies, or zerocopies of any of (a) haplotype (147) in Table 1, (b) a linked haplotypefor haplotype (147) in Table 1, and (c) a substitute haplotype forhaplotype (147) in Table 1; and assigning the individual to the firstage of onset marker group if the individual has one copy or two copiesof any of (a) haplotype (147) in Table 1, (b) a linked haplotype forhaplotype (147) in Table 1, and (c) a substitute haplotype for haplotype(147) in Table 1, and assigning the individual to the second age ofonset marker group if the individual has zero copies of any of (a)haplotype (147) in Table 1, (b) a linked haplotype for haplotype (147)in Table 1, and (c) a substitute haplotype for haplotype (147) inTable
 1. 19. The method of claim 18, wherein the method comprises:determining whether the individual has one copy or two copies, or zerocopies of haplotype (147) in Table 1; and assigning the individual tothe first age of onset marker group if the individual has one copy ortwo copies of haplotype (147) in Table 1, and assigning the individualto the second age of onset marker group if the individual has zerocopies of haplotype (147) in Table
 1. 20. The method of claim 13,wherein the individual is Caucasian.
 21. The method of claim 13, whereinthe linkage disequilibrium between the linked haplotype and at least oneof haplotypes (1)-(764) in Table 1 has a delta squared value selectedfrom the group consisting of at least 0.75, at least 0.80, at least0.85, at least 0.90, at least 0.95, and 1.0.
 22. The method of claim 21,wherein the linked haplotype is for haplotype (147) in Table 1 and thelinkage disequilibrium between the linked haplotype and haplotype (147)in Table 1 has a delta squared value of at least 0.95.
 23. The method ofclaim 13, wherein the linkage disequilibrium between the allele at asubstituting PS in the substitute haplotype and the allele at asubstituted PS in any of haplotypes (1)-(764) in Table 1 has a deltasquared value selected from the group consisting of at least 0.75, least0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0.
 24. Themethod of claim 23, wherein the linkage disequilibrium between theallele at a substituting PS and the allele at a substituted PS inhaplotype (147) in Table 1 has a delta squared value of at least 0.95.25. A kit for determining whether an individual has an age of onsetmarker I or an age of onset marker II, the kit comprising a set of oneor more oligonucleotides designed for identifying at least one of thealleles at each polymorphic site (PS) in a set of one or more PSs,wherein the set of one or more PSs comprises: (1) PS2, PS4, and PS14;(2) PS2, PS4, and PS6; (3) PS2, PS4, PS7, and PS13; (4) PS2, PS3, PS4,and PS6; (5) PS2, PS4, and PS13; (6) PS2, PS4, PS5, and PS13; (7) PS2,PS4, PS6, and PS9; (8) PS2, PS3, PS4, and PS7; (9) PS2, PS4, PS8, andPS13; (10) PS2, PS4, PS11, and PS14; (11) PS2, PS4, PS9, and PS11; (12)PS2, PS4, PS6, and PS14; (13) PS2, PS4, PS7, and PS14; (14) PS2, PS4,PS7, and PS9; (15) PS2, PS4, and PS9; (16) PS2, PS4, PS5, and PS9; (17)PS2, PS4, PS5, and PS14; (18) PS2, PS4, PS8, and PS14; (19) PS2, PS4,PS8, and PS9; (20) PS1, PS2, PS4, and PS13; (21) PS2, PS4, PS6, andPS11; (22) PS2, PS4, PS6, and PS7; (23) PS2, PS4, PS7, and PS11; (24)PS2, PS4, PS12, and PS13; (25) PS2, PS4, PS5, and PS6; 26) PS1, PS2,PS4, and PS9; (27) PS1, PS2, PS4, and PS14; (28) PS2, PS4, and PS7; (29)PS2, PS4, PS6, and PS8; (30) PS2, PS4, PS5, and PS7; (31) PS2, PS4,PS12, and PS14; (32) PS2, PS4, PS9, and PS12; (33) PS2, PS4, PS7, andPS8; (34) PS1, PS2, PS4, and PS6; (35) PS2, PS3, PS4, and PS13; (36)PS1, PS2, PS4, and PS7; (37) PS2, PS4, PS13, and PS14; (38) PS2, PS4,PS9, and PS13; (39) PS2, PS4, PS6, and PS12; (40) PS2, PS4, PS7, andPS12; (41) PS2, PS3, PS4, and PS9; (42) PS2, PS3, PS4, and PS14; (43)PS2, PS4, PS9, and PS14; (44) PS2, PS4, PS11, and PS13; (45) PS2, PS4,PS6, and PS13; (46) PS1, PS2, and PS9; (47) PS1, PS2, PS3, and PS9; (48)PS1, PS2, PS9, and PS12; (49) PS2, PS4, and PS5; (50) PS2, PS4, PS5, andPS8; (51) PS2, PS4, PS5, and PS12; (52) PS2, PS3, PS4, and PS5; (53)PS2, PS4, PS5, and PS11; (54) PS1, PS2, PS4, and PS5; (55) PS4, PS9,PS12, and PS14; (56) PS4, PS9, PS12, and PS13; (57) PS4, PS9, and PS12;(58) PS4, PS6, PS9, and PS12; (59) PS4, PS5, PS6, and PS12; (60) PS4,PS9, PS11, and PS12; (61) PS4, PS7, PS9, and PS12; (62) PS3, PS4, PS9,and PS12; (63) PS4, PS8, PS9, and PS12; (64) PS1, PS4, PS9, and PS12;(65) PS4, PS5, PS9, and PS12; (66) PS1, PS4, PS5, and PS12; (67) PS4,PS5, and PS12; (68) PS4, PS5, PS8, and PS12; (69) PS3, PS4, PS5, andPS12; (70) PS4, PS5, PS11, and PS12; (71) PS1, PS2, PS4, and PS9; (72)PS1, PS2, PS9, and PS11; (73) PS4, PS9, and PS13; (74) PS4, PS9, PS11,and PS14; (75) PS4, PS6, PS9, and PS13; (76) PS4, PS5, PS6, and PS13;(77) PS4, PS9, PS11, and PS13; (78) PS4, PS7, PS9, and PS14; (79) PS4,PS8, PS9, and PS14; (80) PS3, PS4, PS9, and PS14; (81) PS4, PS7, PS9,and PS13; (82) PS4, PS9, PS13, and PS14; (83) PS4, PS8, PS9, and PS13;(84) PS3, PS4, PS9, and PS13; (85) PS4, PS9, and PS14; (86) PS4, PS5,PS9, and PS14; (87) PS4, PS6, PS9, and PS14; (88) PS4, PS5, PS9, andPS13; (89) PS4, PS5, PS6, and PS14; (90) PS4 and PS9; (91) PS4, PS5,PS7, and PS9; (92) PS4, PS5, and PS9; (93) PS3, PS4, and PS9; (94) PS3,PS4, PS7, and PS9; (95) PS4, PS7, PS8, and PS9; (96) PS4, PS8, and PS9;(97) PS4, PS6, PS9, and PS11; (98) PS4, PS5, PS6, and PS11; (99) PS4,PS5, PS6, and PS9; (100) PS4, PS6, PS8, and PS9; (101) PS4, PS5, PS6,and PS8; (102) PS4, PS5, PS9, and PS11; (103) PS3, PS4, PS9, and PS11;(104) PS4, PS8, PS9, and PS11; (105) PS3, PS4, PS5, and PS9; (106) PS4,PS5, PS8, and PS9; (107) PS3, PS4, PS8, and PS9; (108) PS4, PS9, andPS11; (109) PS4, PS7, and PS9; (110) PS3, PS4, PS6, and PS9; (11) PS3,PS4, PS5, and PS6; (112) PS4, PS6, PS7, and PS9; (113) PS4, PS6, andPS9; (114) PS4, PS5, PS6, and PS7; (115) PS4, PS5, and PS6; (116) PS4,PS7, PS9, and PS11; (117) PS4, PS5, PS12, and PS14; (118) PS4, PS5,PS12, and PS13; (119) PS4, PS5, PS7, and PS12; (120) PS1, PS4, PS9, andPS14; (121) PS1, PS4, PS9, and PS13; (122) PS1, PS2, and PS5; (123) PS1,PS2, PS5, and PS9; (124) PS1, PS2, PS3, and PS5; (125) PS1, PS2, PS5,and PS12; (126) PS1, PS4, and PS9; (127) PS1, PS3, PS4, and PS9; (128)PS1, PS4, PS9, and PS11; (129) PS1, PS4, PS7, and PS9; (130) PS1, PS4,PS5, and PS9; (131) PS1, PS4, PS5, and PS6; (132) PS1, PS4, PS6, andPS9; (133) PS1, PS4, PS8, and PS9; (134) PS1 and PS9; (135) PS1, PS3,PS9, and PS12; (136) PS1, PS9, and PS12; (137) PS1, PS3, and PS9; (138)PS4 and PS5; (139) PS3, PS4, and PS5; (140) PS3, PS4, PS5, and PS11;(141) PS4, PS5, and PS11; (142) PS3, PS4, PS5, and PS8; (143) PS4, PS5,and PS8; (144) PS4, PS5, PS8, and PS11; (145) PS1, PS5, PS8, and PS13;(146) PS1, PS5, PS8, and PS14; (147) PS2 and PS4; (148) PS2, PS4, PS11,and PS12; (149) PS1, PS2, PS4, and PS11; (150) PS2, PS4, and PS11; (151)PS2, PS4, PS8, and PS12; (152) PS2, PS4, and PS8; (153) PS2, PS3, PS4,and PS12; (154) PS2, PS3, and PS4; (155) PS1, PS2, PS3, and PS4; (156)PS1, PS2, PS4, and PS8; (157) PS2, PS4, PS8, and PS1; (158) PS1, PS2,PS4, and PS12; (159) PS1, PS2, and PS4; (160) PS2, PS4, and PS12; (161)PS2, PS3, PS4, and PS11; (162) PS2, PS3, PS4, and PS8; (163) PS2, PS4,and PS9; (164) PS2, PS4, PS9, and PS12; (165) PS2, PS3, PS4, and PS9;(166) PS2 and PS9; (167) PS2, PS9, and PS12; (168) PS2, PS3, and PS9;(169) PS2, PS3, PS9, and PS12; (170) PS1 and PS5; (171) PS1, PS5, PS9,and PS12; (172) PS1, PS3, PS5, and PS12; (173) PS1, PS3, PS5, and PS9;(174) PS1, PS5, and PS12; (175) PS1, PS5, and PS9; (176) PS1, PS3, andPS5; (177) PS1, PS4, and PS5; (178) PS1, PS3, PS4, and PS5; (179) PS1,PS4, PS5, and PS11; (180) PS1, PS4, PS5, and PS8; (181) PS4, PS5, andPS14; (182) PS4, PS5, and PS13; (183) PS4, PS5, PS11, and PS14; (184)PS4, PS5, PS7, and PS14; (185) PS4, PS5, PS8, and PS14; (186) PS4, PS5,PS11, and PS13; (187) PS4, PS5, PS7, and PS13; (188) PS4, PS5, PS8, andPS13; (189) PS3, PS4, PS5, and PS14; (190) PS4, PS5, PS13, and PS14;(191) PS3, PS4, PS5, and PS13; (192) PS1, PS2, PS4, and PS5; (193) PS4,PS5, and PS7; (194) PS3, PS4, PS5, and PS7; (195) PS4, PS5, PS7, andPS11; (196) PS4, PS5, PS7, and PS8; (197) PS1, PS8, PS9, and PS13; (198)PS1, PS8, PS9, and PS14; (199) PS1, PS2, PS5, and PS11; (200) PS1, PS4,and PS9; (201) PS1, PS4, PS9, and PS12; (202) PS1, PS3, PS4, and PS9;(203) PS9, PS12, and PS14; (204) PS9, PS12, and PS13; (205) PS6, PS9,PS12, and PS14; (206) PS5, PS6, PS12, and PS14; (207) PS9, PS11, PS12,and PS14; (208) PS3, PS9, PS12, and PS14; (209) PS5, PS9, PS12, andPS14; (210) PS8, PS9, PS12, and PS14; (211) PS7, PS9, PS12, and PS13;(212) PS1, PS9, PS12, and PS14; (213) PS6, PS9, PS12, and PS13; (214)PS5, PS6, PS12, and PS13; (215) PS9, PS11, PS12, and PS13; (216) PS9,PS12, PS13, and PS14; (217) PS5, PS9, PS12, and PS13; (218) PS3, PS9,PS12, and PS13; (219) PS8, PS9, PS12, and PS13; (220) PS7, PS9, PS12,and PS14; (221) PS1, PS9, PS12, and PS13; (222) PS1, PS9, and PS11;(223) PS1, PS9, PS11, and PS12; (224) PS1, PS3, PS9, and PS11; (225) PS9and PS12; (226) PS6, PS9, PS11, and PS12; (227) PS1, PS9, and PS12;(228) PS1, PS7, PS9, and PS12; (229) PS5, PS6, PS11, and PS12; (230)PS5, PS6, PS8, and PS12; (231) PS6, PS7, PS9, and PS12; (232) PS5, PS9,PS11, and PS12; (233) PS3, PS9, PS11, and PS12; (234) PS8, PS9, PS11,and PS12; (235) PS5, PS8, PS9, and PS12; (236) PS1, PS6, PS9, and PS12;(237) PS1, PS5, PS6, and PS12; (238) PS3, PS7, PS9, and PS12; (239) PS1,PS9, PS11, and PS12; (240) PS1, PS5, PS9, and PS12; (241) PS1, PS8, PS9,and PS12; (242) PS7, PS9, and PS12; (243) PS5, PS6, PS9, and PS12; (244)PS3, PS6, PS9, and PS12; (245) PS6, PS8, PS9, and PS12; (246) PS3, PS5,PS6, and PS12; (247) PS3, PS5, PS9, and PS12; (248) PS3, PS8, PS9, andPS12; (249) PS6, PS9, and PS12; (250) PS5, PS6, PS7, and PS12; (251)PS5, PS6, and PS12; (252) PS7, PS9, PS11, and PS12; (253) PS9, PS11, andPS12; (254) PS5, PS7, PS9, and PS12; (255) PS5, PS9, and PS12; (256)PS1, PS3, PS9, and PS12; (257) PS3, PS9, and PS12; (258) PS7, PS8, PS9,and PS12; (259) PS8, PS9, and PS12; (260) PS1, PS4, PS5, and PS14; (261)PS1, PS4, PS5, and PS13; (262) PS1, PS4, PS5, and PS7; (263) PS2, PS4,PS9, and PS11; (264) PS1, PS5, and PS12; (265) PS5 and PS12; (266) PS1,PS5, PS11, and PS12; (267) PS3, PS5, and PS12; (268) PS1, PS3, PS5, andPS12; (269) PS5, PS8, and PS12; (270) PS1, PS5, PS8, and PS12; (271)PS5, PS8, PS11, and PS12; (272) PS3, PS5, PS11, and PS12; (273) PS5,PS11, and PS12; (274) PS3, PS5, PS8, and PS12; (275) PS2, PS9, and PS11;(276) PS2, PS9, PS1, and PS12; (277) PS2, PS3, PS9, and PS11; (278) PS1,PS4, and PS5; (279) PS1, PS4, PS5, and PS12; (280) PS1, PS4, PS5, andPS9; (281) PS1, PS3, PS4, and PS5; (282) PS5, PS8, and PS13; (283) PS3,PS5, PS8, and PS14; (284) PS5, PS8, PS9, and PS14; (285) PS5, PS8, PS13,and PS14; (286) PS3, PS5, PS8, and PS13; (287) PS5, PS8, PS12, and PS14;(288) PS5, PS8, and PS14; (289) PS5, PS8, PS9, and PS13; (290) PS5, PS8,PS12, and PS13; (291) PS2, PS5, PS8, and PS14; (292) PS2, PS5, PS8, andPS13; (293) PS5, PS8, PS11, and PS14; (294) PS5, PS8, PS11, and PS13;(295) PS1, PS5, and PS11; (296) PS1, PS5, PS11, and PS12; (297) PS1,PS5, PS9, and PS11; (298) PS1, PS3, PS5, and PS11; (299) PS9 and PS14;(300) PS9 and PS13; (301) PS5, PS6, PS7, and PS14; (302) PS5, PS6, andPS14; (303) PS5, PS6, PS8, and PS14; (304) PS3, PS6, PS9, and PS13;(305) PS3, PS9, PS11, and PS13; (306) PS6, PS9, PS13, and PS14; (307)PS3, PS7, PS9, and PS13; (308) PS9, PS11, PS13, and PS14; (309) PS3,PS9, and PS13; (310) PS7, PS9, PS13, and PS14; (311) PS3, PS5, PS9, andPS13; (312) PS3, PS9, PS11, and PS14; (313) PS3, PS6, PS9, and PS14;(314) PS3, PS8, PS9, and PS13; (315) PS9, PS13, and PS14; (316) PS5,PS9, PS13, and PS14; (317) PS3, PS7, PS9, and PS14; (318) PS8, PS9,PS13, and PS14; (319) PS3, PS9, and PS14; (320) PS6, PS9, PS11, andPS13; (321) PS3, PS5, PS9, and PS14; (322) PS3, PS8, PS9, and PS14;(323) PS7, PS9, PS11, and PS13; (324) PS6, PS7, PS9, and PS13; (325)PS3, PS5, PS6, and PS13; (326) PS6, PS9, and PS13; (327) PS9, PS11, andPS13; (328) PS5, PS9, PS11, and PS13; (329) PS5, PS6, PS13, and PS14;(330) PS5, PS6, PS9, and PS13; (331) PS6, PS9, PS1, and PS14; (332) PS7,PS9, and PS13; (333) PS8, PS9, PS11, and PS13; (334) PS6, PS8, PS9, andPS13; (335) PS5, PS7, PS9, and PS13; (336) PS7, PS8, PS9, and PS13;(337) PS7, PS9, PS11, and PS14; (338) PS6, PS7, PS9, and PS14; (339)PS3, PS5, PS6, and PS14; (340) PS5, PS9, and PS13; (341) PS6, PS9, andPS14; (342) PS8, PS9, and PS13; (343) PS5, PS8, PS9, and PS13; (344)PS9, PS11, and PS14; (345) PS5, PS9, PS11, and PS14; (346) PS5, PS6,PS9, and PS14; (347) PS7, PS9, and PS14; (348) PS8, PS9, PS11, and PS14;(349) PS6, PS8, PS9, and PS14; (350) PS5, PS7, PS9, and PS14; (351) PS5,PS6, PS11, and PS13; (352) PS7, PS8, PS9, and PS14; (353) PS5, PS6, PS7,and PS13; (354) PS5, PS9, and PS14; (355) PS8, PS9, and PS14; (356) PS5,PS8, PS9, and PS14; (357) PS5, PS6, and PS13; (358) PS5, PS6, PS8, andPS13; (359) PS5, PS6, PS1, and PS14; (360) PS3, PS9, PS13, and PS14;(361) PS9; (362) PS6, PS8, PS9, and PS11; (363) PS5, PS7, PS9, and PS11;(364) PS5, PS6, PS7, and PS9; (365) PS6 and PS9; (366) PS7, PS8, PS9,and PS11; (367) PS6, PS7, PS8, and PS9; (368) PS3, PS5, PS6, and PS8;(369) PS9 and PS11; (370) PS5, PS6, and PS9; (371) PS5, PS9, and PS11;(372) PS7 and PS9; (373) PS6, PS8, and PS9; (374) PS8, PS9, and PS11;(375) PS5, PS7, and PS9; (376) PS5, PS8, PS9, and PS11; (377) PS5, PS6,PS8, and PS9; (378) PS7, PS8, and PS9; (379) PS5 and PS9; (380) PS5,PS7, PS8, and PS9; (381) PS8 and PS9; (382) PS5, PS8, and PS9; (383)PS5, PS6, PS7, and PS11; (384) PS5, PS6, and PS11; (385) PS5, PS6, andPS7; (386) PS5, PS6, PS8, and PS11; (387) PS5 and PS6; (388) PS5, PS6,PS7, and PS8; (389) PS5, PS6, and PS8; (390) PS3, PS6, PS9, and PS11;(391) PS3, PS6, PS7, and PS9; (392) PS3, PS7, PS9, and PS11; (393) PS3,PS6, and PS9; (394) PS3, PS9, and PS11; (395) PS3, PS5, PS6, and PS9;(396) PS3, PS5, PS9, and PS11; (397) PS3, PS6, PS8, and PS9; (398) PS3,PS7, and PS9; (399) PS3, PS8, PS9, and PS11; (400) PS3, PS5, PS7, andPS9; (401) PS3 and PS9; (402) PS3, PS7, PS8, and PS9; (403) PS3, PS5,and PS9; (404) PS3, PS8, and PS9; (405) PS3, PS5, PS8, and PS9; (406)PS6, PS7, PS9, and PS11; (407) PS3, PS5, PS6, and PS11; (408) PS6, PS9,and PS11; (409) PS3, PS5, PS6, and PS7; (410) PS5, PS6, PS9, and PS11;(411) PS3, PS5, and PS6; (412) PS6, PS7, and PS9; (413) PS7, PS9, andPS11; (414) PS9; (415) PS3, PS9, and PS12; (416) PS9 and PS12; (417) PS3and PS9; (418) PS5, PS7, PS12, and PS14; (419) PS5, PS12, and PS13;(420) PS5, PS7, PS12, and PS13; (421) PS5, PS12, PS13, and PS14; (422)PS5, PS8, PS12, and PS13; (423) PS3, PS5, PS12, and PS13; (424) PS5,PS12, and PS14; (425) PS1, PS5, PS12, and PS14; (426) PS5, PS11, PS12,and PS14; (427) PS1, PS5, PS12, and PS13; (428) PS5, PS81, PS12, andPS13; (429) PS5, PS8, PS12, and PS14; (430) PS3, PS5, PS12, and PS14;(431) PS1, PS4, PS9, and PS11; (432) PS8, PS9, and PS13; (433) PS8, PS9,PS1, and PS14; (434) PS3, PS8, PS9, and PS14; (435) PS8, PS9, PS11, andPS13; (436) PS3, PS8, PS9, and PS13; (437) PS8, PS9, PS13, and PS14;(438) PS2, PS8, PS9, and PS14; (439) PS8, PS9, PS12, and PS14; (440)PS8, PS9, and PS14; (441) PS2, PS8, PS9, and PS13; (442) PS8, PS9, PS12,and PS13; (443) PS4 and PS9; (444) PS3, PS4, PS9, and PS12; (445) PS4,PS9, and PS12; (446) PS3, PS4, and PS9; (447) PS1, PS5, PS7, and PS12;(448) PS5, PS7, and PS12; (449) PS3, PS5, PS7, and PS12; (450) PS5, PS7,PS11, and PS12; (451) PS5, PS7, PS8, and PS12; (452) PS2 and PS5; (453)PS2, PS3, PS5, and PS9; (454) PS2, PS5, and PS12; (455) PS2, PS5, andPS9; (456) PS2, PS3, and PS5; (457) PS2, PS5, PS9, and PS12; (458) PS2,PS3, PS5, and PS12; (459) PS2, PS4, and PS5; (460) PS2, PS4, PS5, andPS12; (461) PS2, PS4, PS5, and PS9; (462) PS2, PS3, PS4, and PS5; (463)PS9, PS11, and PS14; (464) PS9, PS11, and PS13; (465) PS3, PS9, PS11,and PS14; (466) PS9, PS11, PS13, and PS14; (467) PS3, PS9, PS11, andPS13; (468) PS9, PS11, PS12, and PS14; (469) PS2, PS9, PS11, and PS14;(470) PS9, PS11, PS12, and PS13; (471) PS2, PS9, PS11, and PS13; (472)PS1, PS9, and PS14; (473) PS1, PS9, and PS13; (474) PS1, PS8, PS9, andPS13; (475) PS1, PS3, PS9, and PS14; (476) PS1, PS5, PS9, and PS14;(477) PS1, PS9, PS13, and PS14; (478) PS1, PS3, PS9, and PS13; (479)PS1, PS6, PS9, and PS14; (480) PS1, PS5, PS9, and PS13; (481) PS1, PS5,PS6, and PS14; (482) PS1, PS6, PS9, and PS13; (483) PS1, PS5, PS6, andPS13; (484) PS1, PS9, PS11, and PS14; (485) PS1, PS7, PS9, and PS14;(486) PS1, PS8, PS9, and PS14; (487) PS1, PS9, PS11, and PS13; (488)PS1, PS7, PS9, and PS13; (489) PS1 and PS9; (490) PS1, PS6, PS7, andPS9; (491) PS1, PS5, PS9, and PS11; (492) PS1, PS8, PS9, and PS11; (493)PS1, PS5, PS8, and PS9; (494) PS1, PS3, PS7, and PS9; (495) PS1, PS3,and PS9; (496) PS1, PS7, and PS9; (497) PS1, PS5, PS6, and PS9; (498)PS1, PS3, PS6, and PS9; (499) PS1, PS6, PS8, and PS9; (500) PS1, PS3,PS5, and PS6; (501) PS1, PS5, PS6, and PS8; (502) PS1, PS3, PS9, andPS11; (503) PS1, PS3, PS5, and PS9; (504) PS1, PS3, PS8, and PS9; (505)PS1, PS6, and PS9; (506) PS1, PS5, and PS6; (507) PS1, PS5, PS6, andPS7; (508) PS1, PS7, PS9, and PS11; (509) PS1, PS9, and PS11; (510) PS1,PS5, PS7, and PS9; (511) PS1, PS5, and PS9; (512) PS1, PS7, PS8, andPS9; (513) PS1, PS8, and PS9; (514) PS1, PS6, PS9, and PS11; (515) PS1,PS5, PS6, and PS11; (516) PS2 and PS14; (517) PS2, PS5, and PS9; (518)PS2, PS3, PS6, and PS7; (519) PS2, PS3, PS7, and PS13; (520) PS1, PS2,and PS14; (521) PS1, PS2, PS7, and PS8; (522) PS2, PS7, PS8, and PS9;(523) PS2, PS9, and PS14; (524) PS2, PS3, PS11, and PS14; (525) PS2,PS3, PS12, and PS14; (526) PS1, PS2, PS6, and PS11; (527) PS1, PS2,PS11, and PS13; (528) PS2, PS9, PS11, and PS13; (529) PS2, PS6, PS9, andPS11; (530) PS1, PS2, PS6, and PS12; (531) PS1, PS2, PS12, and PS13;(532) PS2, PS9, PS12, and PS13; (533) PS2, PS6, PS9, and PS12; (534)PS2, PS3, PS8, and PS9; (535) PS2, PS7, and PS11; (536) PS2, PS5, andPS14; (537) PS2, PS7, and PS12; (538) PS2, PS5, PS11, and PS13; (539)PS2, PS5, PS12, and PS13; (540) PS2, PS6, PS8, and PS13; (541) PS2 andPS9; (542) PS2, PS3, PS6, and PS13; (543) PS1, PS2, PS8, and PS13; (544)PS1, PS2, PS3, and PS7; (545) PS2, PS3, PS7, and PS9; (546) PS1, PS2,PS9, and PS11; (547) PS1, PS2, PS9, and PS12; (548) PS2, PS5, PS7, andPS8; (549) PS2, PS5, PS6, and PS11; (550) PS2, PS7, PS8, and PS14; (551)PS2, PS5, PS6, and PS12; (552) PS2, PS6, PS7, and PS13; (553) PS2, PS3,PS5, and PS7; (554) PS2, PS11, PS13, and PS14; (555) PS2, PS6, PS11, andPS14; (556) PS2, PS12, PS13, and PS14; (557) PS2, PS6, PS12, and PS14;(558) PS1, PS2, PS7, and PS13; (559) PS2, PS3, PS8, and PS14; (560) PS1,PS2, PS6, and PS8; (561) PS2, PS8, PS9, and PS13; (562) PS2, PS6, PS8,and PS9; (563) PS1, PS2, PS3, and PS6; (564) PS1, PS2, PS3, and PS13;(565) PS2, PS3, PS9, and PS13; (566) PS2, PS7, and PS8; (567) PS2, PS6,and PS11; (568) PS2, PS11, and PS13; (569) PS2, PS5, PS6, and PS8; (570)PS2, PS5, PS8, and PS13; (571) PS2, PS12, and PS13; (572) PS2, PS6, andPS12; (573) PS2, PS8, PS13, and PS14; (574) PS2, PS3, PS7, and PS14;(575) PS1, PS2, PS6, and PS7; (576) PS2, PS5, PS9, and PS11; (577) PS2,PS7, PS9, and PS13; (578) PS2, PS5, PS9, and PS12; (579) PS2, PS6, PS7,and PS9; (580) PS1, PS2, PS11, and PS14; (581) PS2, PS9, PS11, and PS14;(582) PS1, PS2, PS12, and PS14; (583) PS2, PS9, PS12, and PS14; (584)PS2, PS3, PS6, and PS9; (585) PS1, PS2, PS8, and PS9; (586) PS2, PS5,PS6, and PS7; (587) PS2, PS5, PS7, and PS13; (588) PS1, PS2, PS3, andPS9; (589) PS2, PS5, PS11, and PS14; (590) PS2, PS8, and PS13; (591)PS2, PS7, PS11, and PS12; (592) PS2, PS3, and PS7; (593) PS2, PS7, PS13,and PS14; (594) PS2, PS5, PS12, and PS14; (595) PS2, PS6, PS8, and PS14;(596) PS2, PS3, PS5, and PS13; (597) PS2, PS3, PS5, and PS6; (598) PS2,PS9, and PS11; (599) PS2, PS5, PS8, and PS9; (600) PS2, PS9, and PS12;(601) PS2, PS3, PS6, and PS14; (602) PS2, PS3, PS13, and PS14; (603)PS1, PS2, PS8, and PS14; (604) PS1, PS2, PS6, and PS13; (605) PS2, PS6,PS9, and PS13; (606) PS1, PS2, PS7, and PS9; (607) PS2, PS7, and PS13;(608) PS2, PS6, and PS8; (609) PS2, PS6, PS7, and PS14; (610) PS1, PS2,PS5, and PS7; (611) PS2, PS5, PS7, and PS9; (612) PS2, PS3, and PS6;(613) PS2, PS3, and PS13; (614) PS1, PS2, PS7, and PS14; (615) PS2, PS8,PS9, and PS14; (616) PS2, PS3, PS5, and PS9; (617) PS1, PS2, PS3, andPS14; (618) PS2, PS3, PS9, and PS14; (619) PS1, PS2, PS9, and PS13;(620) PS1, PS2, PS6, and PS9; (621) PS2, PS6, and PS7; (622) PS2, PS7,PS8, and PS11; (623) PS2, PS11, and PS14; (624) PS2, PS5, PS8, and PS14;(625) PS2, PS7, PS8, and PS12; (626) PS2, PS5, PS6, and PS13; (627) PS2,PS12, and PS14; (628) PS1, PS2, and PS7; (629) PS2, PS11, PS12, andPS13; (630) PS2, PS6, PS1, and PS12; (631) PS2, PS6, PS13, and PS14;(632) PS2, PS8, and PS9; (633) PS2, PS7, PS9, and PS14; (634) PS1, PS2,PS5, and PS13; (635) PS2, PS3, and PS9; (636) PS2, PS5, PS7, and PS14;(637) PS2, PS8, and PS14; (638) PS2, PS6, and PS13; (639) PS2, PS8,PS11, and PS13; (640) PS2, PS7, and PS9; (641) PS2, PS3, PS7, and PS11;(642) PS2, PS8, PS12, and PS13; (643) PS2, PS3, PS5, and PS14; (644)PS2, PS3, PS7, and PS12; (645) PS1, PS2, PS5, and PS6; (646) PS2, PS5,PS6, and PS9; (647) PS2, PS5, PS9, and PS13; (648) PS1, PS2, PS6, andPS14; (649) PS1, PS2, PS13, and PS14; (650) PS2, PS9, PS11, and PS12;(651) PS2, PS9, PS13, and PS14; (652) PS2, PS6, PS9, and PS14; (653)PS2, PS5, and PS7; (654) PS2, PS7, and PS14; (655) PS2, PS7, PS11, andPS13; (656) PS2, PS5, PS13, and PS14; (657) PS2, PS7, PS12, and PS13;(658) PS2, PS6, PS8, and PS11; (659) PS2, PS6, PS8, and PS12; (660) PS2,PS3, PS7, and PS8; (661) PS2, PS3, and PS14; (662) PS1, PS2, and PS6;(663) PS1, PS2, and PS13; (664) PS2, PS6, and PS9; (665) PS2, PS9, andPS13; (666) PS2, PS3, PS6, and PS11; (667) PS2, PS3, PS11, and PS13;(668) PS2, PS3, PS12, and PS13; (669) PS2, PS3, PS6, and PS12; (670)PS1, PS2, PS5, and PS9; (671) PS2 and PS7; (672) PS1, PS2, PS9, andPS14; (673) PS2, PS5, and PS13; (674) PS2, PS6, PS7, and PS11; (675)PS2, PS5, PS6, and PS14; (676) PS2, PS6, PS7, and PS12; (677) PS2, PS11,PS12, and PS14; (678) PS1, PS2, PS7, and PS11; (679) PS1, PS2, PS5, andPS14; (680) PS1, PS2, PS7, and PS12; (681) PS2, PS8, PS9, and PS11;(682) PS2, PS8, PS9, and PS12; (683) PS1, PS2, and PS9; (684) PS2, PS3,PS9, and PS11; (685) PS2, PS3, PS9, and PS12; (686) PS2, PS5, and PS6;(687) PS2, PS7, PS8, and PS13; (688) PS2, PS6, and PS14; (689) PS2,PS13, and PS14; (690) PS2, PS6, PS7, and PS8; (691) PS2, PS8, PS11, andPS14; (692) PS2, PS6, PS1, and PS13; (693) PS2, PS8, PS12, and PS14;(694) PS2, PS6, PS12, and PS13; (695) PS2, PS7, PS9, and PS11; (696)PS2, PS5, PS9, and PS14; (697) PS2, PS7, PS9, and PS12; (698) PS2, PS3,PS6, and PS8; (699) PS2, PS3, PS8, and PS13; (700) PS2 and PS13; (701)PS2, PS5, PS7, and PS11; (702) PS2, PS5, PS7, and PS12; (703) PS2, PS7,PS11, and PS14; (704) PS2, PS7, PS12, and PS14; (705) PS5; (706) PS5,PS8, and PS11; (707) PS3 and PS5; (708) PS3, PS5, and PS11; (709) PS5and PS11; (710) PS3, PS5, and PS8; (711) PS3, PS5, PS8, and PS11; (712)PS5 and PS8; (713) PS5; (714) PS3, PS5, PS9, and PS12; (715) PS5, PS9,and PS12; (716) PS3, PS5, and PS12; (717) PS3, PS5, and PS9; (718) PS5and PS12; (719) PS5 and PS9; (720) PS3 and PS5; (721) PS9 and PS13;(722) PS2, PS9, and PS13; (723) PS3, PS9, PS12, and PS14; (724) PS9,PS12, PS13, and PS14; (725) PS2, PS9, PS12, and PS14; (726) PS3, PS9,PS13, and PS14; (727) PS9, PS12, and PS14; (728) PS2, PS3, PS9, andPS14; (729) PS2, PS9, PS13, and PS14; (730) PS3, PS9, and PS14; (731)PS9, PS13, and PS14; (732) PS2, PS9, and PS14; (733) PS9 and PS14; (734)PS3, PS9, PS12, and PS13; (735) PS2, PS9, PS12, and PS13; (736) PS9,PS12, and PS13; (737) PS2, PS3, PS9, and PS13; (738) PS3, PS9, and PS13;(739) PS1, PS4, PS5, and PS11; (740) PS4, PS8, PS9, and PS13; (741) PS4,PS8, PS9, and PS14; (742) PS2 and PS5; (743) PS2, PS5, PS8, and PS11;(744) PS2, PS3, PS5, and PS11; (745) PS1, PS2, PS5, and PS12; (746) PS2,PS5, and PS12; (747) PS1, PS2, and PS5; (748) PS2, PS3, PS5, and PS8;(749) PS2, PS5, PS11, and PS12; (750) PS1, PS2, PS5, and PS11; (751)PS2, PS5, and PS11; (752) PS2, PS5, PS8, and PS12; (753) PS2, PS3, PS5,and PS12; (754) PS2, PS3, and PS5; (755) PS2, PS5, and PS8; (756) PS1,PS2, PS5, and PS8; (757) PS1, PS2, PS3, and PS5; (758) PS4 and PS5;(759) PS4, PS5, PS9, and PS12; (760) PS3, PS4, PS5, and PS12; (761) PS3,PS4, PS5, and PS9; (762) PS4, PS5, and PS12; (763) PS4, PS5, and PS9;(764) PS3, PS4, and PS5; (765) a set of one or more PSs in a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, or (766) a set ofone or more PSs in a substitute haplotype for any of haplotypes(1)-(764) in Table 1, wherein the enumerated PSs in sets (1)-(766)correspond to the following nucleotide positions in SEQ ID NO:1: PS1,1703; PS2, 12203; PS3, 18873; PS4, 23591; PS5, 25782; PS6, 28361; PS7,28771; PS8, 28845; PS9, 28893; PS11, 32494; PS12, 32626; PS13, 43101;and PS14,
 43168. 26. The kit of claim 25, wherein the kit comprises aset of one or more oligonucleotides designed for identifying at leastone of the alleles at each PS in a set of one or more PSs, wherein theset of one or more PSs is any of: (1) PS2, PS4, and PS14; (2) PS2, PS4,and PS6; (3) PS2, PS4, PS7, and PS13; (4) PS2, PS3, PS4, and PS6; (5)PS2, PS4, and PS13; (6) PS2, PS4, PS5, and PS13; (7) PS2, PS4, PS6, andPS9; (8) PS2, PS3, PS4, and PS7; (9) PS2, PS4, PS8, and PS13; (10) PS2,PS4, PS11, and PS14; (11) PS2, PS4, PS9, and PS11; (12) PS2, PS4, PS6,and PS14; (13) PS2, PS4, PS7, and PS14; (14) PS2, PS4, PS7, and PS9;(15) PS2, PS4, and PS9; (16) PS2, PS4, PS5, and PS9; (17) PS2, PS4, PS5,and PS14; (18) PS2, PS4, PS8, and PS14; (19) PS2, PS4, PS8, and PS9;(20) PS1, PS2, PS4, and PS13; (21) PS2, PS4, PS6, and PS11; (22) PS2,PS4, PS6, and PS7; (23) PS2, PS4, PS7, and PS11; (24) PS2, PS4, PS12,and PS13; (25) PS2, PS4, PS5, and PS6; 26) PS1, PS2, PS4, and PS9; (27)PS1, PS2, PS4, and PS14; (28) PS2, PS4, and PS7; (29) PS2, PS4, PS6, andPS8; (30) PS2, PS4, PS5, and PS7; (31) PS2, PS4, PS12, and PS14; (32)PS2, PS4, PS9, and PS12; (33) PS2, PS4, PS7, and PS8; (34) PS1, PS2,PS4, and PS6; (35) PS2, PS3, PS4, and PS13; (36) PS1, PS2, PS4, and PS7;(37) PS2, PS4, PS13, and PS14; (38) PS2, PS4, PS9, and PS13; (39) PS2,PS4, PS6, and PS12; (40) PS2, PS4, PS7, and PS12; (41) PS2, PS3, PS4,and PS9; (42) PS2, PS3, PS4, and PS14; (43) PS2, PS4, PS9, and PS14;(44) PS2, PS4, PS11, and PS13; (45) PS2, PS4, PS6, and PS13; (46) PS1,PS2, and PS9; (47) PS1, PS2, PS3, and PS9; (48) PS1, PS2, PS9, and PS12;(49) PS2, PS4, and PS5; (50) PS2, PS4, PS5, and PS8; (51) PS2, PS4, PS5,and PS12; (52) PS2, PS3, PS4, and PS5; (53) PS2, PS4, PS5, and PS11;(54) PS1, PS2, PS4, and PS5; (55) PS4, PS9, PS12, and PS14; (56) PS4,PS9, PS12, and PS13; (57) PS4, PS9, and PS12; (58) PS4, PS6, PS9, andPS12; (59) PS4, PS5, PS6, and PS12; (60) PS4, PS9, PS11, and PS12; (61)PS4, PS7, PS9, and PS12; (62) PS3, PS4, PS9, and PS12; (63) PS4, PS8,PS9, and PS12; (64) PS1, PS4, PS9, and PS12; (65) PS4, PS5, PS9, andPS12; (66) PS1, PS4, PS5, and PS12; (67) PS4, PS5, and PS12; (68) PS4,PS5, PS8, and PS12; (69) PS3, PS4, PS5, and PS12; (70) PS4, PS5, PS11,and PS12; (71) PS1, PS2, PS4, and PS9; (72) PS1, PS2, PS9, and PS11;(73) PS4, PS9, and PS13; (74) PS4, PS9, PS11, and PS14; (75) PS4, PS6,PS9, and PS13; (76) PS4, PS5, PS6, and PS13; (77) PS4, PS9, PS1, andPS13; (78) PS4, PS7, PS9, and PS14; (79) PS4, PS8, PS9, and PS14; (80)PS3, PS4, PS9, and PS14; (81) PS4, PS7, PS9, and PS13; (82) PS4, PS9,PS13, and PS14; (83) PS4, PS8, PS9, and PS13; (84) PS3, PS4, PS9, andPS13; (85) PS4, PS9, and PS14; (86) PS4, PS5, PS9, and PS14; (87) PS4,PS6, PS9, and PS14; (88) PS4, PS5, PS9, and PS13; (89) PS4, PS5, PS6,and PS14; (90) PS4 and PS9; (91) PS4, PS5, PS7, and PS9; (92) PS4, PS5,and PS9; (93) PS3, PS4, and PS9; (94) PS3, PS4, PS7, and PS9; (95) PS4,PS7, PS8, and PS9; (96) PS4, PS8, and PS9; (97) PS4, PS6, PS9, and PS11;(98) PS4, PS5, PS6, and PS11; (99) PS4, PS5, PS6, and PS9; (100) PS4,PS6, PS8, and PS9; (101) PS4, PS5, PS6, and PS8; (102) PS4, PS5, PS9,and PS11; (103) PS3, PS4, PS9, and PS11; (104) PS4, PS8, PS9, and PS11;(105) PS3, PS4, PS5, and PS9; (106) PS4, PS5, PS8, and PS9; (107) PS3,PS4, PS8, and PS9; (108) PS4, PS9, and PS11; (109) PS4, PS7, and PS9;(110) PS3, PS4, PS6, and PS9; (111) PS3, PS4, PS5, and PS6; (112) PS4,PS6, PS7, and PS9; (113) PS4, PS6, and PS9; (114) PS4, PS5, PS6, andPS7; (115) PS4, PS5, and PS6; (116) PS4, PS7, PS9, and PS11; (117) PS4,PS5, PS12, and PS14; (118) PS4, PS5, PS12, and PS13; (119) PS4, PS5,PS7, and PS12; (120) PS1, PS4, PS9, and PS14; (121) PS1, PS4, PS9, andPS13; (122) PS1, PS2, and PS5; (123) PS1, PS2, PS5, and PS9; (124) PS1,PS2, PS3, and PS5; (125) PS1, PS2, PS5, and PS12; (126) PS1, PS4, andPS9; (127) PS1, PS3, PS4, and PS9; (128) PS1, PS4, PS9, and PS11; (129)PS1, PS4, PS7, and PS9; (130) PS1, PS4, PS5, and PS9; (131) PS1, PS4,PS5, and PS6; (132) PS1, PS4, PS6, and PS9; (133) PS1, PS4, PS8, andPS9; (134) PS1 and PS9; (135) PS1, PS3, PS9, and PS12; (136) PS1, PS9,and PS12; (137) PS1, PS3, and PS9; (138) PS4 and PS5; (139) PS3, PS4,and PS5; (140) PS3, PS4, PS5, and PS11; (141) PS4, PS5, and PS11; (142)PS3, PS4, PS5, and PS8; (143) PS4, PS5, and PS8; (144) PS4, PS5, PS8,and PS11; (145) PS1, PS5, PS8, and PS13; (146) PS1, PS5, PS8, and PS14;(147) PS2 and PS4; (148) PS2, PS4, PS11, and PS12; (149) PS1, PS2, PS4,and PS11; (150) PS2, PS4, and PS11; (151) PS2, PS4, PS8, and PS12; (152)PS2, PS4, and PS8; (153) PS2, PS3, PS4, and PS12; (154) PS2, PS3, andPS4; (155) PS1, PS2, PS3, and PS4; (156) PS1, PS2, PS4, and PS8; (157)PS2, PS4, PS8, and PS11; (158) PS1, PS2, PS4, and PS12; (159) PS1, PS2,and PS4; (160) PS2, PS4, and PS12; (161) PS2, PS3, PS4, and PS11; (162)PS2, PS3, PS4, and PS8; (163) PS2, PS4, and PS9; (164) PS2, PS4, PS9,and PS12; (165) PS2, PS3, PS4, and PS9; (166) PS2 and PS9; (167) PS2,PS9, and PS12; (168) PS2, PS3, and PS9; (169) PS2, PS3, PS9, and PS12;(170) PS1 and PS5; (171) PS1, PS5, PS9, and PS12; (172) PS1, PS3, PS5,and PS12; (173) PS1, PS3, PS5, and PS9; (174) PS1, PS5, and PS12; (175)PS1, PS5, and PS9; (176) PS1, PS3, and PS5; (177) PS1, PS4, and PS5;(178) PS1, PS3, PS4, and PS5; (179) PS1, PS4, PS5, and PS11; (180) PS1,PS4, PS5, and PS8; (181) PS4, PS5, and PS14; (182) PS4, PS5, and PS13;(183) PS4, PS5, PS11, and PS14; (184) PS4, PS5, PS7, and PS14; (185)PS4, PS5, PS8, and PS14; (186) PS4, PS5, PS11, and PS13; (187) PS4, PS5,PS7, and PS13; (188) PS4, PS5, PS8, and PS13; (189) PS3, PS4, PS5, andPS14; (190) PS4, PS5, PS13, and PS14; (191) PS3, PS4, PS5, and PS13;(192) PS1, PS2, PS4, and PS5; (193) PS4, PS5, and PS7; (194) PS3, PS4,PS5, and PS7; (195) PS4, PS5, PS7, and PS11; (196) PS4, PS5, PS7, andPS8; (197) PS1, PS8, PS9, and PS13; (198) PS1, PS8, PS9, and PS14; (199)PS1, PS2, PS5, and PS11; (200) PS1, PS4, and PS9; (201) PS1, PS4, PS9,and PS12; (202) PS1, PS3, PS4, and PS9; (203) PS9, PS12, and PS14; (204)PS9, PS12, and PS13; (205) PS6, PS9, PS12, and PS14; (206) PS5, PS6,PS12, and PS14; (207) PS9, PS11, PS12, and PS14; (208) PS3, PS9, PS12,and PS14; (209) PS5, PS9, PS12, and PS14; (210) PS8, PS9, PS12, andPS14; (211) PS7, PS9, PS12, and PS13; (212) PS1, PS9, PS12, and PS14;(213) PS6, PS9, PS12, and PS13; (214) PS5, PS6, PS12, and PS13; (215)PS9, PS1, PS12, and PS13; (216) PS9, PS12, PS13, and PS14; (217) PS5,PS9, PS12, and PS13; (218) PS3, PS9, PS12, and PS13; (219) PS8, PS9,PS12, and PS13; (220) PS7, PS9, PS12, and PS14; (221) PS1, PS9, PS12,and PS13; (222) PS1, PS9, and PS11; (223) PS1, PS9, PS11, and PS12;(224) PS1, PS3, PS9, and PS11; (225) PS9 and PS12; (226) PS6, PS9, PS11,and PS12; (227) PS1, PS9, and PS12; (228) PS1, PS7, PS9, and PS12; (229)PS5, PS6, PS11, and PS12; (230) PS5, PS6, PS8, and PS12; (231) PS6, PS7,PS9, and PS12; (232) PS5, PS9, PS11, and PS12; (233) PS3, PS9, PS11, andPS12; (234) PS8, PS9, PS11, and PS12; (235) PS5, PS8, PS9, and PS12;(236) PS1, PS6, PS9, and PS12; (237) PS1, PS5, PS6, and PS12; (238) PS3,PS7, PS9, and PS12; (239) PS1, PS9, PS11, and PS12; (240) PS1, PS5, PS9,and PS12; (241) PS1, PS8, PS9, and PS12; (242) PS7, PS9, and PS12; (243)PS5, PS6, PS9, and PS12; (244) PS3, PS6, PS9, and PS12; (245) PS6, PS8,PS9, and PS12; (246) PS3, PS5, PS6, and PS12; (247) PS3, PS5, PS9, andPS12; (248) PS3, PS8, PS9, and PS12; (249) PS6, PS9, and PS12; (250)PS5, PS6, PS7, and PS12; (251) PS5, PS6, and PS12; (252) PS7, PS9, PS11,and PS12; (253) PS9, PS11, and PS12; (254) PS5, PS7, PS9, and PS12;(255) PS5, PS9, and PS12; (256) PS1, PS3, PS9, and PS12; (257) PS3, PS9,and PS12; (258) PS7, PS8, PS9, and PS12; (259) PS8, PS9, and PS12; (260)PS1, PS4, PS5, and PS14; (261) PS1, PS4, PS5, and PS13; (262) PS1, PS4,PS5, and PS7; (263) PS2, PS4, PS9, and PS81; (264) PS1, PS5, and PS12;(265) PS5 and PS12; (266) PS1, PS5, PS11, and PS12; (267) PS3, PS5, andPS12; (268) PS1, PS3, PS5, and PS12; (269) PS5, PS8, and PS12; (270)PS1, PS5, PS8, and PS12; (271) PS5, PS8, PS11, and PS12; (272) PS3, PS5,PS11, and PS12; (273) PS5, PS1, and PS12; (274) PS3, PS5, PS8, and PS12;(275) PS2, PS9, and PS11; (276) PS2, PS9, PS11, and PS12; (277) PS2,PS3, PS9, and PS11; (278) PS1, PS4, and PS5; (279) PS1, PS4, PS5, andPS12; (280) PS1, PS4, PS5, and PS9; (281) PS1, PS3, PS4, and PS5; (282)PS5, PS8, and PS13; (283) PS3, PS5, PS8, and PS14; (284) PS5, PS8, PS9,and PS14; (285) PS5, PS8, PS13, and PS14; (286) PS3, PS5, PS8, and PS13;(287) PS5, PS8, PS12, and PS14; (288) PS5, PS8, and PS14; (289) PS5,PS8, PS9, and PS13; (290) PS5, PS8, PS12, and PS13; (291) PS2, PS5, PS8,and PS14; (292) PS2, PS5, PS8, and PS13; (293) PS5, PS8, PS11, and PS14;(294) PS5, PS8, PS11, and PS13; (295) PS1, PS5, and PS11; (296) PS1,PS5, PS11, and PS12; (297) PS1, PS5, PS9, and PS11; (298) PS1, PS3, PS5,and PS11; (299) PS9 and PS14; (300) PS9 and PS13; (301) PS5, PS6, PS7,and PS14; (302) PS5, PS6, and PS14; (303) PS5, PS6, PS8, and PS14; (304)PS3, PS6, PS9, and PS13; (305) PS3, PS9, PS11, and PS13; (306) PS6, PS9,PS13, and PS14; (307) PS3, PS7, PS9, and PS13; (308) PS9, PS11, PS13,and PS14; (309) PS3, PS9, and PS13; (310) PS7, PS9, PS13, and PS14;(311) PS3, PS5, PS9, and PS13; (312) PS3, PS9, PS11, and PS14; (313)PS3, PS6, PS9, and PS14; (314) PS3, PS8, PS9, and PS13; (315) PS9, PS13,and PS14; (316) PS5, PS9, PS13, and PS14; (317) PS3, PS7, PS9, and PS14;(318) PS8, PS9, PS13, and PS14; (319) PS3, PS9, and PS14; (320) PS6,PS9, PS11, and PS13; (321) PS3, PS5, PS9, and PS14; (322) PS3, PS8, PS9,and PS14; (323) PS7, PS9, PS11, and PS13; (324) PS6, PS7, PS9, and PS13;(325) PS3, PS5, PS6, and PS13; (326) PS6, PS9, and PS13; (327) PS9,PS11, and PS13; (328) PS5, PS9, PS11, and PS13; (329) PS5, PS6, PS13,and PS14; (330) PS5, PS6, PS9, and PS13; (331) PS6, PS9, PS1, and PS14;(332) PS7, PS9, and PS13; (333) PS8, PS9, PS11, and PS13; (334) PS6,PS8, PS9, and PS13; (335) PS5, PS7, PS9, and PS13; (336) PS7, PS8, PS9,and PS13; (337) PS7, PS9, PS11, and PS14; (338) PS6, PS7, PS9, and PS14;(339) PS3, PS5, PS6, and PS14; (340) PS5, PS9, and PS13; (341) PS6, PS9,and PS14; (342) PS8, PS9, and PS13; (343) PS5, PS8, PS9, and PS13; (344)PS9, PS11, and PS14; (345) PS5, PS9, PS11, and PS14; (346) PS5, PS6,PS9, and PS14; (347) PS7, PS9, and PS14; (348) PS8, PS9, PS11, and PS14;(349) PS6, PS8, PS9, and PS14; (350) PS5, PS7, PS9, and PS14; (351) PS5,PS6, PS11, and PS13; (352) PS7, PS8, PS9, and PS14; (353) PS5, PS6, PS7,and PS13; (354) PS5, PS9, and PS14; (355) PS8, PS9, and PS14; (356) PS5,PS8, PS9, and PS14; (357) PS5, PS6, and PS13; (358) PS5, PS6, PS8, andPS13; (359) PS5, PS6, PS11, and PS14; (360) PS3, PS9, PS13, and PS14;(361) PS9; (362) PS6, PS8, PS9, and PS11; (363) PS5, PS7, PS9, and PS11;(364) PS5, PS6, PS7, and PS9; (365) PS6 and PS9; (366) PS7, PS8, PS9,and PS11; (367) PS6, PS7, PS8, and PS9; (368) PS3, PS5, PS6, and PS8;(369) PS9 and PS11; (370) PS5, PS6, and PS9; (371) PS5, PS9, and PS11;(372) PS7 and PS9; (373) PS6, PS8, and PS9; (374) PS8, PS9, and PS11;(375) PS5, PS7, and PS9; (376) PS5, PS8, PS9, and PS11; (377) PS5, PS6,PS8, and PS9; (378) PS7, PS8, and PS9; (379) PS5 and PS9; (380) PS5,PS7, PS8, and PS9; (381) PS8 and PS9; (382) PS5, PS8, and PS9; (383)PS5, PS6, PS7, and PS11; (384) PS5, PS6, and PS11; (385) PS5, PS6, andPS7; (386) PS5, PS6, PS8, and PS11; (387) PS5 and PS6; (388) PS5, PS6,PS7, and PS8; (389) PS5, PS6, and PS8; (390) PS3, PS6, PS9, and PS11;(391) PS3, PS6, PS7, and PS9; (392) PS3, PS7, PS9, and PS11; (393) PS3,PS6, and PS9; (394) PS3, PS9, and PS11; (395) PS3, PS5, PS6, and PS9;(396) PS3, PS5, PS9, and PS11; (397) PS3, PS6, PS8, and PS9; (398) PS3,PS7, and PS9; (399) PS3, PS8, PS9, and PS11; (400) PS3, PS5, PS7, andPS9; (401) PS3 and PS9; (402) PS3, PS7, PS8, and PS9; (403) PS3, PS5,and PS9; (404) PS3, PS8, and PS9; (405) PS3, PS5, PS8, and PS9; (406)PS6, PS7, PS9, and PS11; (407) PS3, PS5, PS6, and PS11; (408) PS6, PS9,and PS11; (409) PS3, PS5, PS6, and PS7; (410) PS5, PS6, PS9, and PS11;(411) PS3, PS5, and PS6; (412) PS6, PS7, and PS9; (413) PS7, PS9, andPS11; (414) PS9; (415) PS3, PS9, and PS12; (416) PS9 and PS12; (417) PS3and PS9; (418) PS5, PS7, PS12, and PS14; (419) PS5, PS12, and PS13;(420) PS5, PS7, PS12, and PS13; (421) PS5, PS12, PS13, and PS14; (422)PS5, PS8, PS12, and PS13; (423) PS3, PS5, PS12, and PS13; (424) PS5,PS12, and PS14; (425) PS1, PS5, PS12, and PS14; (426) PS5, PS11, PS12,and PS14; (427) PS1, PS5, PS12, and PS13; (428) PS5, PS11, PS12, andPS13; (429) PS5, PS8, PS12, and PS14; (430) PS3, PS5, PS12, and PS14;(431) PS1, PS4, PS9, and PS11; (432) PS8, PS9, and PS13; (433) PS8, PS9,PS11, and PS14; (434) PS3, PS8, PS9, and PS14; (435) PS8, PS9, PS11, andPS13; (436) PS3, PS8, PS9, and PS13; (437) PS8, PS9, PS13, and PS14;(438) PS2, PS8, PS9, and PS14; (439) PS8, PS9, PS12, and PS14; (440)PS8, PS9, and PS14; (441) PS2, PS8, PS9, and PS13; (442) PS8, PS9, PS12,and PS13; (443) PS4 and PS9; (444) PS3, PS4, PS9, and PS12; (445) PS4,PS9, and PS12; (446) PS3, PS4, and PS9; (447) PS1, PS5, PS7, and PS12;(448) PS5, PS7, and PS12; (449) PS3, PS5, PS7, and PS12; (450) PS5, PS7,PS11, and PS12; (451) PS5, PS7, PS8, and PS12; (452) PS2 and PS5; (453)PS2, PS3, PS5, and PS9; (454) PS2, PS5, and PS12; (455) PS2, PS5, andPS9; (456) PS2, PS3, and PS5; (457) PS2, PS5, PS9, and PS12; (458) PS2,PS3, PS5, and PS12; (459) PS2, PS4, and PS5; (460) PS2, PS4, PS5, andPS12; (461) PS2, PS4, PS5, and PS9; (462) PS2, PS3, PS4, and PS5; (463)PS9, PS11, and PS14; (464) PS9, PS11, and PS13; (465) PS3, PS9, PS11,and PS14; (466) PS9, PS11, PS13, and PS14; (467) PS3, PS9, PS11, andPS13; (468) PS9, PS11, PS12, and PS14; (469) PS2, PS9, PS11, and PS14;(470) PS9, PS11, PS12, and PS13; (471) PS2, PS9, PS11, and PS13; (472)PS1, PS9, and PS14; (473) PS1, PS9, and PS13; (474) PS1, PS8, PS9, andPS13; (475) PS1, PS3, PS9, and PS14; (476) PS1, PS5, PS9, and PS14;(477) PS1, PS9, PS13, and PS14; (478) PS1, PS3, PS9, and PS13; (479)PS1, PS6, PS9, and PS14; (480) PS1, PS5, PS9, and PS13; (481) PS1, PS5,PS6, and PS14; (482) PS1, PS6, PS9, and PS13; (483) PS1, PS5, PS6, andPS13; (484) PS1, PS9, PS11, and PS14; (485) PS1, PS7, PS9, and PS14;(486) PS1, PS8, PS9, and PS14; (487) PS1, PS9, PS11, and PS13; (488)PS1, PS7, PS9, and PS13; (489) PS1 and PS9; (490) PS1, PS6, PS7, andPS9; (491) PS1, PS5, PS9, and PS11; (492) PS1, PS8, PS9, and PS11; (493)PS1, PS5, PS8, and PS9; (494) PS1, PS3, PS7, and PS9; (495) PS1, PS3,and PS9; (496) PS1, PS7, and PS9; (497) PS1, PS5, PS6, and PS9; (498)PS1, PS3, PS6, and PS9; (499) PS1, PS6, PS8, and PS9; (500) PS1, PS3,PS5, and PS6; (501) PS1, PS5, PS6, and PS8; (502) PS1, PS3, PS9, andPS11; (503) PS1, PS3, PS5, and PS9; (504) PS1, PS3, PS8, and PS9; (505)PS1, PS6, and PS9; (506) PS1, PS5, and PS6; (507) PS1, PS5, PS6, andPS7; (508) PS1, PS7, PS9, and PS11; (509) PS1, PS9, and PS11; (510) PS1,PS5, PS7, and PS9; (511) PS1, PS5, and PS9; (512) PS1, PS7, PS8, andPS9; (513) PS1, PS8, and PS9; (514) PS1, PS6, PS9, and PS11; (515) PS1,PS5, PS6, and PS11; (516) PS2 and PS14; (517) PS2, PS5, and PS9; (518)PS2, PS3, PS6, and PS7; (519) PS2, PS3, PS7, and PS13; (520) PS1, PS2,and PS14; (521) PS1, PS2, PS7, and PS8; (522) PS2, PS7, PS8, and PS9;(523) PS2, PS9, and PS14; (524) PS2, PS3, PS11, and PS14; (525) PS2,PS3, PS12, and PS14; (526) PS1, PS2, PS6, and PS1; (527) PS1, PS2, PS1,and PS13; (528) PS2, PS9, PS11, and PS13; (529) PS2, PS6, PS9, and PS11;(530) PS1, PS2, PS6, and PS12; (531) PS1, PS2, PS12, and PS13; (532)PS2, PS9, PS12, and PS13; (533) PS2, PS6, PS9, and PS12; (534) PS2, PS3,PS8, and PS9; (535) PS2, PS7, and PS11; (536) PS2, PS5, and PS14; (537)PS2, PS7, and PS12; (538) PS2, PS5, PS11, and PS13; (539) PS2, PS5,PS12, and PS13; (540) PS2, PS6, PS8, and PS13; (541) PS2 and PS9; (542)PS2, PS3, PS6, and PS13; (543) PS1, PS2, PS8, and PS13; (544) PS1, PS2,PS3, and PS7; (545) PS2, PS3, PS7, and PS9; (546) PS1, PS2, PS9, andPS11; (547) PS1, PS2, PS9, and PS12; (548) PS2, PS5, PS7, and PS8; (549)PS2, PS5, PS6, and PS11; (550) PS2, PS7, PS8, and PS14; (551) PS2, PS5,PS6, and PS12; (552) PS2, PS6, PS7, and PS13; (553) PS2, PS3, PS5, andPS7; (554) PS2, PS11, PS13, and PS14; (555) PS2, PS6, PS11, and PS14;(556) PS2, PS12, PS13, and PS14; (557) PS2, PS6, PS12, and PS14; (558)PS1, PS2, PS7, and PS13; (559) PS2, PS3, PS8, and PS14; (560) PS1, PS2,PS6, and PS8; (561) PS2, PS8, PS9, and PS13; (562) PS2, PS6, PS8, andPS9; (563) PS1, PS2, PS3, and PS6; (564) PS1, PS2, PS3, and PS13; (565)PS2, PS3, PS9, and PS13; (566) PS2, PS7, and PS8; (567) PS2, PS6, andPS1; (568) PS2, PS1, and PS13; (569) PS2, PS5, PS6, and PS8; (570) PS2,PS5, PS8, and PS13; (571) PS2, PS12, and PS13; (572) PS2, PS6, and PS12;(573) PS2, PS8, PS13, and PS14; (574) PS2, PS3, PS7, and PS14; (575)PS1, PS2, PS6, and PS7; (576) PS2, PS5, PS9, and PS11; (577) PS2, PS7,PS9, and PS13; (578) PS2, PS5, PS9, and PS12; (579) PS2, PS6, PS7, andPS9; (580) PS1, PS2, PS11, and PS14; (581) PS2, PS9, PS11, and PS14;(582) PS1, PS2, PS12, and PS14; (583) PS2, PS9, PS12, and PS14; (584)PS2, PS3, PS6, and PS9; (585) PS1, PS2, PS8, and PS9; (586) PS2, PS5,PS6, and PS7; (587) PS2, PS5, PS7, and PS13; (588) PS1, PS2, PS3, andPS9; (589) PS2, PS5, PS11, and PS14; (590) PS2, PS8, and PS13; (591)PS2, PS7, PS11, and PS12; (592) PS2, PS3, and PS7; (593) PS2, PS7, PS13,and PS14; (594) PS2, PS5, PS12, and PS14; (595) PS2, PS6, PS8, and PS14;(596) PS2, PS3, PS5, and PS13; (597) PS2, PS3, PS5, and PS6; (598) PS2,PS9, and PS11; (599) PS2, PS5, PS8, and PS9; (600) PS2, PS9, and PS12;(601) PS2, PS3, PS6, and PS14; (602) PS2, PS3, PS13, and PS14; (603)PS1, PS2, PS8, and PS14; (604) PS1, PS2, PS6, and PS13; (605) PS2, PS6,PS9, and PS13; (606) PS1, PS2, PS7, and PS9; (607) PS2, PS7, and PS13;(608) PS2, PS6, and PS8; (609) PS2, PS6, PS7, and PS14; (610) PS1, PS2,PS5, and PS7; (611) PS2, PS5, PS7, and PS9; (612) PS2, PS3, and PS6;(613) PS2, PS3, and PS13; (614) PS1, PS2, PS7, and PS14; (615) PS2, PS8,PS9, and PS14; (616) PS2, PS3, PS5, and PS9; (617) PS1, PS2, PS3, andPS14; (618) PS2, PS3, PS9, and PS14; (619) PS1, PS2, PS9, and PS13;(620) PS1, PS2, PS6, and PS9; (621) PS2, PS6, and PS7; (622) PS2, PS7,PS8, and PS11; (623) PS2, PS11, and PS14; (624) PS2, PS5, PS8, and PS14;(625) PS2, PS7, PS8, and PS12; (626) PS2, PS5, PS6, and PS13; (627) PS2,PS12, and PS14; (628) PS1, PS2, and PS7; (629) PS2, PS11, PS12, andPS13; (630) PS2, PS6, PS11, and PS12; (631) PS2, PS6, PS13, and PS14;(632) PS2, PS8, and PS9; (633) PS2, PS7, PS9, and PS14; (634) PS1, PS2,PS5, and PS13; (635) PS2, PS3, and PS9; (636) PS2, PS5, PS7, and PS14;(637) PS2, PS8, and PS14; (638) PS2, PS6, and PS13; (639) PS2, PS8,PS11, and PS13; (640) PS2, PS7, and PS9; (641) PS2, PS3, PS7, and PS11;(642) PS2, PS8, PS12, and PS13; (643) PS2, PS3, PS5, and PS14; (644)PS2, PS3, PS7, and PS12; (645) PS1, PS2, PS5, and PS6; (646) PS2, PS5,PS6, and PS9; (647) PS2, PS5, PS9, and PS13; (648) PS1, PS2, PS6, andPS14; (649) PS1, PS2, PS13, and PS14; (650) PS2, PS9, PS11, and PS12;(651) PS2, PS9, PS13, and PS14; (652) PS2, PS6, PS9, and PS14; (653)PS2, PS5, and PS7; (654) PS2, PS7, and PS14; (655) PS2, PS7, PS11, andPS13; (656) PS2, PS5, PS13, and PS14; (657) PS2, PS7, PS12, and PS13;(658) PS2, PS6, PS8, and PS11; (659) PS2, PS6, PS8, and PS12; (660) PS2,PS3, PS7, and PS8; (661) PS2, PS3, and PS14; (662) PS1, PS2, and PS6;(663) PS1, PS2, and PS13; (664) PS2, PS6, and PS9; (665) PS2, PS9, andPS13; (666) PS2, PS3, PS6, and PS11; (667) PS2, PS3, PS11, and PS13;(668) PS2, PS3, PS12, and PS13; (669) PS2, PS3, PS6, and PS12; (670)PS1, PS2, PS5, and PS9; (671) PS2 and PS7; (672) PS1, PS2, PS9, andPS14; (673) PS2, PS5, and PS13; (674) PS2, PS6, PS7, and PS11; (675)PS2, PS5, PS6, and PS14; (676) PS2, PS6, PS7, and PS12; (677) PS2, PS11,PS12, and PS14; (678) PS1, PS2, PS7, and PS11; (679) PS1, PS2, PS5, andPS14; (680) PS1, PS2, PS7, and PS12; (681) PS2, PS8, PS9, and PS11;(682) PS2, PS8, PS9, and PS12; (683) PS1, PS2, and PS9; (684) PS2, PS3,PS9, and PS11; (685) PS2, PS3, PS9, and PS12; (686) PS2, PS5, and PS6;(687) PS2, PS7, PS8, and PS13; (688) PS2, PS6, and PS14; (689) PS2,PS13, and PS14; (690) PS2, PS6, PS7, and PS8; (691) PS2, PS8, PS11, andPS14; (692) PS2, PS6, PS11, and PS13; (693) PS2, PS8, PS12, and PS14;(694) PS2, PS6, PS12, and PS13; (695) PS2, PS7, PS9, and PS11; (696)PS2, PS5, PS9, and PS14; (697) PS2, PS7, PS9, and PS12; (698) PS2, PS3,PS6, and PS8; (699) PS2, PS3, PS8, and PS13; (700) PS2 and PS13; (701)PS2, PS5, PS7, and PS11; (702) PS2, PS5, PS7, and PS12; (703) PS2, PS7,PS11, and PS14; (704) PS2, PS7, PS12, and PS14; (705) PS5; (706) PS5,PS8, and PS11; (707) PS3 and PS5; (708) PS3, PS5, and PS11; (709) PS5and PS11; (710) PS3, PS5, and PS8; (711) PS3, PS5, PS8, and PS11; (712)PS5 and PS8; (713) PS5; (714) PS3, PS5, PS9, and PS12; (715) PS5, PS9,and PS12; (716) PS3, PS5, and PS12; (717) PS3, PS5, and PS9; (718) PS5and PS12; (719) PS5 and PS9; (720) PS3 and PS5; (721) PS9 and PS13;(722) PS2, PS9, and PS13; (723) PS3, PS9, PS12, and PS14; (724) PS9,PS12, PS13, and PS14; (725) PS2, PS9, PS12, and PS14; (726) PS3, PS9,PS13, and PS14; (727) PS9, PS12, and PS14; (728) PS2, PS3, PS9, andPS14; (729) PS2, PS9, PS13, and PS14; (730) PS3, PS9, and PS14; (731)PS9, PS13, and PS14; (732) PS2, PS9, and PS14; (733) PS9 and PS14; (734)PS3, PS9, PS12, and PS13; (735) PS2, PS9, PS12, and PS13; (736) PS9,PS12, and PS13; (737) PS2, PS3, PS9, and PS13; (738) PS3, PS9, and PS13;(739) PS1, PS4, PS5, and PS11; (740) PS4, PS8, PS9, and PS13; (741) PS4,PS8, PS9, and PS14; (742) PS2 and PS5; (743) PS2, PS5, PS8, and PS11;(744) PS2, PS3, PS5, and PS11; (745) PS1, PS2, PS5, and PS12; (746) PS2,PS5, and PS12; (747) PS1, PS2, and PS5; (748) PS2, PS3, PS5, and PS8;(749) PS2, PS5, PS11, and PS12; (750) PS1, PS2, PS5, and PS11; (751)PS2, PS5, and PS11; (752) PS2, PS5, PS8, and PS12; (753) PS2, PS3, PS5,and PS12; (754) PS2, PS3, and PS5; (755) PS2, PS5, and PS8; (756) PS1,PS2, PS5, and PS8; (757) PS1, PS2, PS3, and PS5; (758) PS4 and PS5;(759) PS4, PS5, PS9, and PS12; (760) PS3, PS4, PS5, and PS12; (761) PS3,PS4, PS5, and PS9; (762) PS4, PS5, and PS12; (763) PS4, PS5, and PS9;(764) PS3, PS4, and PS5; (765) a set of one or more PSs in a linkedhaplotype for any of haplotypes (1)-(764) in Table 1, and (766) a set ofone or more PSs in a substitute haplotype for any of haplotypes(1)-(764) in Table 1, wherein the enumerated PSs in sets (1)-(766)correspond to the following nucleotide positions in SEQ ID NO:1: PS1,106; PS2, 110; PS3, 172; PS5, 536; PS6, 555; PS7, 731; PS9, 787; PS10,827.
 27. The kit of claim 25, wherein the set of one or moreoligonucleotides is designed for identifying both alleles at each PS inthe set of one or more PSs.
 28. The kit of claim 25, wherein the set ofone or more PSs is (147), (765), or (766), wherein if the set is (765),then the linked haplotype is a linked haplotype for haplotype (147) inTable 1, and wherein if the set is (766), then the substitute haplotypeis a substitute haplotype for haplotype (147) in Table
 1. 29. The kit ofclaim 28, wherein the set of one or more PSs is (147).
 30. The kit ofclaim 25, wherein the individual is Caucasian.
 31. The kit of claim 25,which further comprises a manual with instructions for (a) performingone or more reactions on a human nucleic acid sample to identify theallele or alleles present in the individual at each PS in the set of oneor more PSs, and (b) determining if the individual has an age of onsetmarker I or an age of onset marker II based on the identified allele oralleles.
 32. The kit of claim 25, wherein the linkage disequilibriumbetween the linked haplotype and at least one of haplotypes (1)-(764) inTable 1 has a delta squared value selected from the group consisting ofat least 0.75, at least 0.80, at least 0.85, at least 0.90, at least0.95, and 1.0.
 33. The kit of claim 25, wherein the set of one or morePSs is (147) or (765), wherein if the set is (765), then the linkedhaplotype is a linked haplotype for haplotype (147) in Table 1 and thelinkage disequilibrium between the linked haplotype and haplotype (147)in Table 1 has a delta squared value of at least 0.95.
 34. The kit ofclaim 25, wherein the linkage disequilibrium between the allele at asubstituting PS in the substitute haplotype and the allele at asubstituted PS in any of haplotypes (1)-(764) in Table 1 has a deltasquared value selected from the group consisting of at least 0.75, atleast 0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0. 35.The kit of claim 25, wherein the set of one or more PSs is (147) or(766), wherein if the set is (766), then the substitute haplotype is asubstitute haplotype for haplotype (147) in Table 1 and the linkagedisequilibrium between the allele at a substituting PS in the substitutehaplotype and the allele at a substituted PS in haplotype (147) in Table1 has a delta squared value of at least 0.95.
 36. The kit of claim 25,wherein at least one oligonucleotide in the set of one or moreoligonucleotides is an allele-specific oligonucleotide (ASO) probecomprising a nucleotide sequence, wherein the sequence is any of SEQ IDNOS:2-14 and their complements.
 37. The kit of claim 36, wherein the setof one or more PSs is (147) and the at least one oligonucleotide in theset of one or more oligonucleotides is a first ASO probe, a second ASOprobe, a third probe, and a fourth probe, wherein the first ASO probecomprises a nucleotide sequence, wherein the sequence is SEQ ID NO:3 orits complement, wherein Y in SEQ ID NO:3 is T, wherein the second ASOprobe comprises a nucleotide sequence, wherein the sequence is SEQ IDNO:3 or its complement, wherein Y in SEQ ID NO:3 is C, wherein the thirdASO probe comprises a nucleotide sequence, wherein the sequence is SEQID NO:5 or its complement, wherein R in SEQ ID NO:5 is G, and whereinthe fourth ASO probe comprises a nucleotide sequence, wherein thesequence is SEQ ID NO:5 or its complement, wherein R in SEQ ID NO:5 isA.
 38. The kit of claim 25, wherein at least one oligonucleotide in theset of one or more oligonucleotides is a primer-extensionoligonucleotide comprising a nucleotide sequence, wherein the sequenceis any of SEQ ID NOS:15-66.
 39. The kit of claim 38, wherein the set ofone or more PSs is (147) and the at least one oligonucleotide in the setof one or more oligonucleotides is a first primer-extensionoligonucleotide and a second primer-extension oligonucleotide, whereinthe first primer extension oligonucleotide comprises a nucleotidesequence, wherein the sequence is any of SEQ ID NO:42 and SEQ ID NO:55,and wherein the second primer-extension oligonucleotide comprises anucleotide sequence, wherein the sequence is any of SEQ ID NO:44 and SEQID NO:57.
 40. A method for delaying the onset of Alzheimer's Disease(AD) in an individual at risk for developing AD, the method comprising:determining whether the individual has an age of onset marker I or anage of onset marker II; and choosing a treatment for the individualbased upon the results of the determining step.
 41. The method of claim40, wherein if the individual has an age of onset marker I, then thechosen treatment is prescribing to the individual a compound effectivein delaying the onset of AD, at an age below that of the lowerconfidence interval of the least square mean of age of onset for the ageof onset marker I, and wherein if the individual has an age of onsetmarker II, then the chosen treatment is prescribing to the individual acompound effective in delaying the onset of AD, at an age below that ofthe lower confidence interval of the least square mean of age of onsetfor the age of onset marker II.
 42. The method of claim 40, wherein thedetermining step comprises consulting a data repository that stateswhether the individual has an age of onset marker I or an age of onsetmarker II.
 43. The method of claim 42, wherein said data repository isthe individual's medical records or a medical data card.
 44. A methodfor predicting the age of onset of Alzheimer's Disease (AD) in anindividual at risk for developing AD, the method comprising: determiningwhether the individual has an age of onset marker I or an age of onsetmarker II; and making an age of onset prediction based on the results ofthe determining step.
 45. The method of claim 44, wherein if theindividual is determined to have an age of onset marker I, then theprediction is that the individual will develop AD between 71.9 and 81,and if the individual is determined to have an age of onset marker II,then the prediction is that the individual will develop AD between 64.1and 71.3.
 46. The method of claim 44, wherein the determining stepcomprises consulting a data repository that states whether theindividual has an age of onset marker I or an age of onset marker II.47. The method of claim 46, wherein the data repository is theindividual's medical records or a medical data card.
 48. An article ofmanufacture, comprising a pharmaceutical formulation and at least oneindicium identifying a population for whom the pharmaceuticalformulation is indicated, wherein the pharmaceutical formulationcomprises, as at least one active ingredient, a compound effective indelaying the onset of Alzheimer's Disease (AD), and wherein theidentified population is at risk for developing AD and is partially orwholly defined by having an age of onset marker I or an age of onsetmarker II.
 49. The article of manufacture of claim 48, wherein marketingof the pharmaceutical formulation is regulated and the indiciumcomprises the approved label for the pharmaceutical formulation.
 50. Thearticle of manufacture of claim 48, wherein the compound is present inthe pharmaceutical formulation at an amount effective to delay the onsetof AD.
 51. The article of manufacture of claim 48, wherein the age ofonset marker I is one copy or two copies of any of (a) haplotype (147)in Table 1, (b) a linked haplotype for haplotype (147) in Table 1, and(c) a substitute haplotype for haplotype (147) in Table 1, and the ageof onset marker II is zero copies of any of (a) haplotype (147) in Table1, (b) a linked haplotype for haplotype (147) in Table 1, and (c) asubstitute haplotype for haplotype (147) in Table
 1. 52. The article ofmanufacture of claim 51, wherein the linkage disequilibrium between thelinked haplotype and haplotype (147) in Table 1 has a delta squaredvalue selected from the group consisting of at least 0.75, at least0.80, at least 0.85, at least 0.90, at least 0.95, and 1.0.
 53. Thearticle of manufacture of claim 52, wherein the delta squared value isat least 0.95.
 54. The article of manufacture of claim 51, wherein thelinkage disequilibrium between the allele at a substituting PS in thesubstitute haplotype and the allele at a substituted PS in haplotype(147) in Table 1 has a delta squared value selected from the groupconsisting of at least 0.75, least 0.80, at least 0.85, at least 0.90,at least 0.95, and 1.0.
 55. The article of manufacture of claim 54,wherein the delta squared value is at least 0.95.
 56. The article ofmanufacture of claim 48, further comprising an additional indiciumidentifying the population.
 57. The article of manufacture of claim 56,wherein the pharmaceutical formulation is a tablet or capsule and theadditional indicium comprises the color or shape of the tablet orcapsule.
 58. The article of manufacture of claim 56, wherein thepharmaceutical formulation is a tablet or capsule and the additionalindicium comprises a symbol stamped on the tablet or capsule.
 59. Thearticle of manufacture of claim 48, wherein the identified population isfurther defined as being Caucasian.
 60. An article of manufacture,comprising packaging material and a pharmaceutical formulation containedwithin the packaging material, wherein the pharmaceutical formulationcomprises, as at least one active ingredient, a compound effective indelaying the onset of Alzheimer's Disease (AD), and wherein thepackaging material comprises a label which states that thepharmaceutical formulation is indicated for a population at risk fordeveloping AD that is partially or wholly defined by having a age ofonset marker I or age of onset marker II.
 61. The article of manufactureof claim 60 wherein the age of onset marker I is one copy or two copiesof any of (a) haplotype (147) in Table 1, (b) a linked haplotype forhaplotype (147) in Table 1, and (c) a substitute haplotype for haplotype(147) in Table 1, and the age of onset marker II is zero copies of anyof (a) haplotype (147) in Table 1, (b) a linked haplotype for haplotype(147) in Table 1, and (c) a substitute haplotype for haplotype (147) inTable
 1. 62. The article of manufacture of claim 61, wherein the age ofonset marker I is one copy or two copies of haplotype (147) in Table 1,and the age of onset marker II is zero copies of haplotype (147) inTable
 1. 63. The article of manufacture of claim 61, wherein the linkagedisequilibrium between the linked haplotype and haplotype (147) in Table1 has a delta squared value selected from the group consisting of atleast 0.75, least 0.80, at least 0.85, at least 0.90, at least 0.95, and1.0.
 64. The article of manufacture of claim 63, wherein the deltasquared value is at least 0.95.
 65. The article of manufacture of claim61, wherein the linkage disequilibrium between the allele at asubstituting PS in the substitute haplotype and the allele at asubstituted PS in haplotype (147) in Table 1 has a delta squared valueselected from the group consisting of at least 0.75, least 0.80, atleast 0.85, at least 0.90, at least 0.95, and 1.0.
 66. The article ofmanufacture of claim 65, wherein the delta squared value is at least0.95.
 67. A method for manufacturing a drug product, the methodcomprising combining in a package a pharmaceutical formulationcomprising, as at least one active ingredient, a compound effective indelaying the onset of Alzheimer's Disease (AD), and a label which statesthat the pharmaceutical formulation is indicated for a population atrisk for developing AD that is partially or wholly defined by having anage of onset marker I or an age of onset marker II.
 68. The method ofclaim 67, wherein the age of onset marker I is one copy or two copies ofany of (a) haplotype (147) in Table 1, (b) a linked haplotype forhaplotype (147) in Table 1, and (c) a substitute haplotype for haplotype(147) in Table 1, and the age of onset marker II is zero copies of anyof (a) haplotype (147) in Table 1, (b) a linked haplotype for haplotype(147) in Table 1, and (c) a substitute haplotype for haplotype (147) inTable
 1. 69. The method of claim 68, wherein the linkage disequilibriumbetween the linked haplotype and haplotype (147) in Table 1 has a deltasquared value selected from the group consisting of at least 0.75, atleast 0.90, at least 0.95, and 1.0.
 70. The method of claim 69, whereinthe delta squared value is at least 0.95.
 71. The method of claim 68,wherein the linkage disequilibrium between the allele at a substitutingPS in the substitute haplotype and the allele at a substituted PS inhaplotype (147) in Table 1 has a delta squared value selected from thegroup consisting of at least 0.75, least 0.80, at least 0.85, at least0.90, at least 0.95, and 1.0.
 72. The method of claim 71, wherein thedelta squared value is at least 0.95.
 73. The method of claim 67,wherein the label further states that the indicated population isfurther defined as being Caucasian.